JP6661766B2 - Pharmaceutical composition containing a 7-azaindoline-2-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient - Google Patents
Pharmaceutical composition containing a 7-azaindoline-2-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient Download PDFInfo
- Publication number
- JP6661766B2 JP6661766B2 JP2018524367A JP2018524367A JP6661766B2 JP 6661766 B2 JP6661766 B2 JP 6661766B2 JP 2018524367 A JP2018524367 A JP 2018524367A JP 2018524367 A JP2018524367 A JP 2018524367A JP 6661766 B2 JP6661766 B2 JP 6661766B2
- Authority
- JP
- Japan
- Prior art keywords
- carbon atoms
- group
- cancer
- substituted
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000003839 salts Chemical class 0.000 title claims description 34
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 24
- 239000004480 active ingredient Substances 0.000 title claims description 10
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical class C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 93
- 125000004432 carbon atom Chemical group C* 0.000 claims description 79
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- 206010028980 Neoplasm Diseases 0.000 claims description 49
- 238000004519 manufacturing process Methods 0.000 claims description 45
- 201000011510 cancer Diseases 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- -1 R 14 Chemical compound 0.000 claims description 27
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 206010027476 Metastases Diseases 0.000 claims description 15
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 14
- 230000009401 metastasis Effects 0.000 claims description 13
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 12
- 206010009944 Colon cancer Diseases 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 10
- 208000029742 colonic neoplasm Diseases 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- 230000009400 cancer invasion Effects 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 210000001072 colon Anatomy 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical group CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 6
- 206010061424 Anal cancer Diseases 0.000 claims description 5
- 208000007860 Anus Neoplasms Diseases 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 5
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 5
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 5
- 201000011165 anus cancer Diseases 0.000 claims description 5
- 201000007455 central nervous system cancer Diseases 0.000 claims description 5
- 208000025997 central nervous system neoplasm Diseases 0.000 claims description 5
- 201000010175 gallbladder cancer Diseases 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 208000026037 malignant tumor of neck Diseases 0.000 claims description 5
- 201000000849 skin cancer Diseases 0.000 claims description 5
- 206010046766 uterine cancer Diseases 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 210000000988 bone and bone Anatomy 0.000 claims description 3
- 210000000481 breast Anatomy 0.000 claims description 3
- 210000003238 esophagus Anatomy 0.000 claims description 3
- 210000003734 kidney Anatomy 0.000 claims description 3
- 210000000867 larynx Anatomy 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- 210000000496 pancreas Anatomy 0.000 claims description 3
- 230000000849 parathyroid Effects 0.000 claims description 3
- 210000003800 pharynx Anatomy 0.000 claims description 3
- 210000002307 prostate Anatomy 0.000 claims description 3
- 210000001685 thyroid gland Anatomy 0.000 claims description 3
- 210000003932 urinary bladder Anatomy 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical group 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- WEYVCQFUGFRXOM-UHFFFAOYSA-N perazine Chemical compound C1CN(C)CCN1CCCN1C2=CC=CC=C2SC2=CC=CC=C21 WEYVCQFUGFRXOM-UHFFFAOYSA-N 0.000 claims 2
- 229960002195 perazine Drugs 0.000 claims 2
- 210000002784 stomach Anatomy 0.000 claims 2
- 210000002105 tongue Anatomy 0.000 claims 2
- 235000011167 hydrochloric acid Nutrition 0.000 claims 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- 239000000243 solution Substances 0.000 description 37
- 210000004027 cell Anatomy 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- 239000000203 mixture Substances 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 15
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 description 13
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 12
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 11
- 229960001796 sunitinib Drugs 0.000 description 11
- 201000010099 disease Diseases 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 8
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 8
- 230000005907 cancer growth Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- CLQOBOAKNXTWQK-UHFFFAOYSA-N 3,3-dimethyl-1h-pyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CC=C2C(C)(C)C(=O)NC2=N1 CLQOBOAKNXTWQK-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 5
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 5
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 5
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 5
- 201000002528 pancreatic cancer Diseases 0.000 description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- FPGGLMIYNLQOID-UHFFFAOYSA-N 3h-pyridin-2-one Chemical compound O=C1CC=CC=N1 FPGGLMIYNLQOID-UHFFFAOYSA-N 0.000 description 4
- JVYGCTCRERAFMX-UHFFFAOYSA-N 5-(chloromethyl)-2,4-dimethyl-3-phenylmethoxypyridine hydrochloride Chemical compound Cl.Cc1ncc(CCl)c(C)c1OCc1ccccc1 JVYGCTCRERAFMX-UHFFFAOYSA-N 0.000 description 4
- TTZDLIXBHFOMJL-UHFFFAOYSA-N 5-hydroxy-4,6-dimethyl-1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C2C(=NC=1C)NC(C2)=O)C TTZDLIXBHFOMJL-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- NWBJQTUWFDURJH-UHFFFAOYSA-N ethyl 2-(5-hydroxy-4,6-dimethylpyridin-3-yl)acetate Chemical compound OC=1C(=C(C=NC=1C)CC(=O)OCC)C NWBJQTUWFDURJH-UHFFFAOYSA-N 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NMZCOYLXIIZTPO-FLIBITNWSA-N (3Z)-3-hexylidene-5-hydroxy-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound C(/CCCCC)=C\1/C(NC2=NC(=C(C(=C2/1)C)O)C)=O NMZCOYLXIIZTPO-FLIBITNWSA-N 0.000 description 3
- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 206010062129 Tongue neoplasm Diseases 0.000 description 3
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 201000006134 tongue cancer Diseases 0.000 description 3
- HWUCMHJWFIJOTF-UHFFFAOYSA-N (4,6-dimethyl-5-phenylmethoxypyridin-3-yl)methanol Chemical compound CC1=NC=C(CO)C(C)=C1OCC1=CC=CC=C1 HWUCMHJWFIJOTF-UHFFFAOYSA-N 0.000 description 2
- XBPJVSRTTKVMEN-UHFFFAOYSA-N 2,4-dimethyl-1h-pyrrole-3-carboxylic acid Chemical compound CC1=CNC(C)=C1C(O)=O XBPJVSRTTKVMEN-UHFFFAOYSA-N 0.000 description 2
- DCIBPWRHNNNCFD-UHFFFAOYSA-N 2-(4,6-dimethyl-5-phenylmethoxypyridin-3-yl)acetonitrile Chemical compound C(C1=CC=CC=C1)OC=1C(=C(C=NC=1C)CC#N)C DCIBPWRHNNNCFD-UHFFFAOYSA-N 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 231100000111 LD50 Toxicity 0.000 description 2
- 206010023825 Laryngeal cancer Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- JWXSLMOFTVLPOW-POHAHGRESA-N OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C=1SC=CC=1)=O)C Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C=1SC=CC=1)=O)C JWXSLMOFTVLPOW-POHAHGRESA-N 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 206010043515 Throat cancer Diseases 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 239000002257 antimetastatic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003966 growth inhibitor Substances 0.000 description 2
- JARKCYVAAOWBJS-UHFFFAOYSA-N hexanal Chemical compound CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- QZKKOQQIVLXUEI-UHFFFAOYSA-N hydron;5-(hydroxymethyl)-2,4-dimethylpyridin-3-ol;chloride Chemical compound Cl.CC1=NC=C(CO)C(C)=C1O QZKKOQQIVLXUEI-UHFFFAOYSA-N 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 235000019833 protease Nutrition 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical compound [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- BBQCCDAXHOFCPD-UYRXBGFRSA-N (3Z)-3-(2,2-diphenylethylidene)-5-hydroxy-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound C1(=CC=CC=C1)C(\C=C\1/C(NC2=NC(=C(C(=C2/1)C)O)C)=O)C1=CC=CC=C1 BBQCCDAXHOFCPD-UYRXBGFRSA-N 0.000 description 1
- BUHKIKXWQUJDMH-XFFZJAGNSA-N (3Z)-3-(2-ethylbutylidene)-5-hydroxy-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound C(C)C(\C=C\1/C(NC2=NC(=C(C(=C2/1)C)O)C)=O)CC BUHKIKXWQUJDMH-XFFZJAGNSA-N 0.000 description 1
- MLHTWMHZFAKFDI-WQLSENKSSA-N (3Z)-3-(cyclohexylmethylidene)-5-hydroxy-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound C1(CCCCC1)\C=C\1/C(NC2=NC(=C(C(=C2/1)C)O)C)=O MLHTWMHZFAKFDI-WQLSENKSSA-N 0.000 description 1
- ZRSUWFIUVYGATF-POHAHGRESA-N (3Z)-3-(furan-2-ylmethylidene)-5-hydroxy-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound O1C(=CC=C1)\C=C\1/C(NC2=NC(=C(C(=C2/1)C)O)C)=O ZRSUWFIUVYGATF-POHAHGRESA-N 0.000 description 1
- UBTUWTIUQUNYBV-YHYXMXQVSA-N (3Z)-3-(furan-3-ylmethylidene)-5-hydroxy-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound O1C=C(C=C1)\C=C\1/C(NC2=NC(=C(C(=C2/1)C)O)C)=O UBTUWTIUQUNYBV-YHYXMXQVSA-N 0.000 description 1
- MENNKNPADFUZSN-JYRVWZFOSA-N (3Z)-3-[(2,5-dimethoxyphenyl)methylidene]-5-hydroxy-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound COC1=C(\C=C\2/C(NC3=NC(=C(C(=C3/2)C)O)C)=O)C=C(C=C1)OC MENNKNPADFUZSN-JYRVWZFOSA-N 0.000 description 1
- JTVNMCJAYYRKNW-GHXNOFRVSA-N (3Z)-3-[(4-chlorophenyl)methylidene]-5-hydroxy-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound ClC1=CC=C(\C=C\2/C(NC3=NC(=C(C(=C3/2)C)O)C)=O)C=C1 JTVNMCJAYYRKNW-GHXNOFRVSA-N 0.000 description 1
- VWRRLAICXXBXDZ-GHXNOFRVSA-N (3Z)-3-[(4-fluorophenyl)methylidene]-5-hydroxy-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound FC1=CC=C(\C=C\2/C(NC3=NC(=C(C(=C3/2)C)O)C)=O)C=C1 VWRRLAICXXBXDZ-GHXNOFRVSA-N 0.000 description 1
- IFRXKNKUZULECW-XFFZJAGNSA-N (3Z)-5-hydroxy-3-[(2-hydroxyphenyl)methylidene]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=C(C=CC=C1)O)=O)C IFRXKNKUZULECW-XFFZJAGNSA-N 0.000 description 1
- MGHNKIISPHYRNJ-WQLSENKSSA-N (3Z)-5-hydroxy-3-[(2-methoxyphenyl)methylidene]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=C(C=CC=C1)OC)=O)C MGHNKIISPHYRNJ-WQLSENKSSA-N 0.000 description 1
- LNLQQHBLZVAVLN-JYRVWZFOSA-N (3Z)-5-hydroxy-3-[(3-methoxyphenyl)methylidene]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=CC(=CC=C1)OC)=O)C LNLQQHBLZVAVLN-JYRVWZFOSA-N 0.000 description 1
- YQQVVNCXUWLQGO-JYRVWZFOSA-N (3Z)-5-hydroxy-3-[(4-methoxyphenyl)methylidene]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=CC=C(C=C1)OC)=O)C YQQVVNCXUWLQGO-JYRVWZFOSA-N 0.000 description 1
- OVYRTKJLAXWFBU-YVMONPNESA-N (3Z)-5-hydroxy-4,6-dimethyl-3-(1,3-thiazol-2-ylmethylidene)-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C=1SC=CN=1)=O)C OVYRTKJLAXWFBU-YVMONPNESA-N 0.000 description 1
- VZKRPXPIVXSIQT-YBEGLDIGSA-N (3Z)-5-hydroxy-4,6-dimethyl-3-(naphthalen-2-ylmethylidene)-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=CC2=CC=CC=C2C=C1)=O)C VZKRPXPIVXSIQT-YBEGLDIGSA-N 0.000 description 1
- FFLCCEDCNXMBII-XFFZJAGNSA-N (3Z)-5-hydroxy-4,6-dimethyl-3-(pyridin-2-ylmethylidene)-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=NC=CC=C1)=O)C FFLCCEDCNXMBII-XFFZJAGNSA-N 0.000 description 1
- QHNKEWGVKNULNS-WDZFZDKYSA-N (3Z)-5-hydroxy-4,6-dimethyl-3-(pyridin-3-ylmethylidene)-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C=1C=NC=CC=1)=O)C QHNKEWGVKNULNS-WDZFZDKYSA-N 0.000 description 1
- DULHSXTXDCUMPW-XFFZJAGNSA-N (3Z)-5-hydroxy-4,6-dimethyl-3-(pyridin-4-ylmethylidene)-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=CC=NC=C1)=O)C DULHSXTXDCUMPW-XFFZJAGNSA-N 0.000 description 1
- CSKXBCHNPARCGH-ZROIWOOFSA-N (3Z)-5-hydroxy-4,6-dimethyl-3-(quinolin-2-ylmethylidene)-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=NC2=CC=CC=C2C=C1)=O)C CSKXBCHNPARCGH-ZROIWOOFSA-N 0.000 description 1
- LEIMCFGKMVXNQF-XFFZJAGNSA-N (3Z)-5-hydroxy-4,6-dimethyl-3-[(2-nitrophenyl)methylidene]-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=C(C=CC=C1)[N+](=O)[O-])=O)C LEIMCFGKMVXNQF-XFFZJAGNSA-N 0.000 description 1
- LUSLGRZJBKXLQG-JYRVWZFOSA-N (3Z)-5-hydroxy-4,6-dimethyl-3-[(4-methylphenyl)methylidene]-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=CC=C(C=C1)C)=O)C LUSLGRZJBKXLQG-JYRVWZFOSA-N 0.000 description 1
- OBSXAQTWKIBHEZ-GHXNOFRVSA-N (3Z)-5-hydroxy-4,6-dimethyl-3-[(4-nitrophenyl)methylidene]-1H-pyrrolo[2,3-b]pyridin-2-one Chemical compound OC=1C(=C/2C(=NC=1C)NC(\C\2=C/C1=CC=C(C=C1)[N+](=O)[O-])=O)C OBSXAQTWKIBHEZ-GHXNOFRVSA-N 0.000 description 1
- XGQXULJHBWKUJY-LYIKAWCPSA-N (z)-but-2-enedioic acid;n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide Chemical compound OC(=O)\C=C/C(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C XGQXULJHBWKUJY-LYIKAWCPSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- JVKRKMWZYMKVTQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JVKRKMWZYMKVTQ-UHFFFAOYSA-N 0.000 description 1
- VXZBYIWNGKSFOJ-UHFFFAOYSA-N 2-[4-[5-(2,3-dihydro-1H-inden-2-ylamino)pyrazin-2-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC=1N=CC(=NC=1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 VXZBYIWNGKSFOJ-UHFFFAOYSA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000255789 Bombyx mori Species 0.000 description 1
- YTQNSFTVNHYUBQ-UHFFFAOYSA-N C1(=CC=CC=C1)N=NC(=NNC=1SC(=C(N1)C)C)C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)N=NC(=NNC=1SC(=C(N1)C)C)C1=CC=CC=C1 YTQNSFTVNHYUBQ-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102000005600 Cathepsins Human genes 0.000 description 1
- 108010084457 Cathepsins Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000002820 allylidene group Chemical group [H]C(=[*])C([H])=C([H])[H] 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000037417 hyperactivation Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000004962 larynx cancer Diseases 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Description
本発明は、７−アザインドリン−２−オン誘導体又はその薬学的に許容される塩を有効成分として含有する癌疾患の予防又は治療用医薬組成物に関するものである。 The present invention relates to a pharmaceutical composition for preventing or treating cancer diseases, comprising a 7-azaindoline-2-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
癌患者の死の主な原因の一つは転移（metastasis）であり、現の臨床的に使用される化学療法又は免疫療法が癌患者の生残率の増加に貢献できない理由でもある。 One of the major causes of cancer patient death is metastasis, which is why current clinically used chemotherapy or immunotherapy cannot contribute to the increased survival of cancer patients.
ほとんどの固形癌の転移は、癌細胞が最初に現れる部位で増殖が行われ、癌塊がより大きくなるにつれて、新生血管を介した成長と増殖に必要な栄養及び酸素を腫瘍に供給する。その後、癌細胞は癌塊から分離され、血管を通って身体の他の部位に移動し、次に２次部位に定着し、そこで細胞増殖が再度起こる。即ち、腫瘍に浸透する新生血管は、移転性癌細胞に転移する機会を与え、これは癌細胞が移転するための重要な助けとなる（非特許文献１）。 Most solid cancer metastases grow at the site where the cancer cells first appear, and as the cancer mass grows larger, it supplies the tumor with nutrients and oxygen necessary for growth and proliferation through neovascularization. Thereafter, the cancer cells are separated from the cancer mass, migrate through blood vessels to other parts of the body, and then colonize secondary sites where cell growth occurs again. That is, new blood vessels that penetrate the tumor provide an opportunity to metastasize to metastatic cancer cells, which is an important aid for cancer cells to metastasize (Non-Patent Document 1).
血管新生と同様に、癌の成長及び転移において核心的な役割を果たすシグナル分子は、ＶＥＧＦ（vascular endothelial growth factor）及びその受容体を含む増殖因子である。成長因子受容体の核心の部分である受容体チロシンキナーゼ（ＲＴＫ）は、細胞の生存、分化、遊走、増殖などの様残な細胞活性に関与している。このようなＲＴＫが様々な癌細胞における異常調節及び過活性化によって、癌の成長と悪性進行において核心的な役割を果たす。ＶＥＧＦ受容体２（ＫＤＲ）チロシンキナーゼを含む様々な種類のＲＴＫが癌細胞の生存、増殖を調節し、血管内皮細胞の増殖、遊走、及び管形成を促進することによって血管新生を誘導する。癌の場合は、ＶＥＧＦ以外にも様々な種類の成長因子を分泌され、癌細胞及び血管内皮のＲＴＫを刺激し、腫瘍の成長及び血管を通した転移をもたらす。このように、ＫＤＲチロシンキナーゼのみ抑制する場合、癌細胞は、これに対する抵抗性を示し、抑制された癌の成長が再開される。従って、様々な種類の成長因子に対する受容体ＲＴＫの抑制は、抗癌剤を開発するための効率的な戦略である。代表的な例は、マルチ標的ＲＴＫ抑制剤であるスニチニブ（sunitinib）（商品名：Sutent（マレイン酸スニチニブ））である。 Like angiogenesis, signal molecules that play a pivotal role in cancer growth and metastasis are growth factors including VEGF (vascular endothelial growth factor) and its receptor. Receptor tyrosine kinases (RTKs), which are at the heart of the growth factor receptor, are involved in residual cell activities such as cell survival, differentiation, migration, and proliferation. Such RTKs play a key role in cancer growth and malignant progression by dysregulation and hyperactivation in various cancer cells. Various types of RTKs, including VEGF receptor 2 (KDR) tyrosine kinase, regulate cancer cell survival, proliferation, and induce angiogenesis by promoting vascular endothelial cell proliferation, migration, and tube formation. In the case of cancer, various types of growth factors other than VEGF are secreted, and the RTKs of cancer cells and vascular endothelium are stimulated, resulting in tumor growth and metastasis through blood vessels. Thus, when only the KDR tyrosine kinase is suppressed, the cancer cells show resistance thereto, and the suppressed growth of the cancer is resumed. Thus, inhibition of receptor RTKs for various types of growth factors is an efficient strategy for developing anti-cancer agents. A representative example is sunitinib (trade name: Sutent (sunitinib maleate)), which is a multi-target RTK inhibitor.
癌細胞が血管を介して身体の他の部位に移動するためには、癌細胞は浸潤過程を経なければならない。このために、癌細胞は過発現プロテイナーゼを分泌して、細胞外マトリックスを分解する。このような分解酵素には、マトリックスメタロプロテイナーゼ（ＭＭＰｓ）、カテプシン（cathepsins）及び種々プロテイナーゼ（proteinases）等がある。多くの種類のＭＭＰがあり、ＭＭＰは、癌の周辺組織中の線維芽細胞及びマクロファージなどの細胞及び癌細胞から分泌され、癌の浸潤及び転移を媒介する最も重要な酵素群の一つである。ＶＥＧＦＲ２に対するＶＥＧＦの結合による細胞内シグナルは、ＭＭＰ発現を抑制する（非特許文献２）、また、ＭＭＰはＶＥＧＦ又はＶＥＧＦＲ２の発現調節にも関与している（非特許文献３、４）。 For cancer cells to migrate to other parts of the body via blood vessels, they must undergo an invasion process. To this end, cancer cells secrete overexpressed proteinases and degrade the extracellular matrix. Such degrading enzymes include matrix metalloproteinases (MMPs), cathepsins, and various proteinases. There are many types of MMPs, which are secreted from cells such as fibroblasts and macrophages in cancer surrounding tissues and cancer cells and are one of the most important enzymes that mediate cancer invasion and metastasis . An intracellular signal due to the binding of VEGF to VEGFR2 suppresses MMP expression (Non-Patent Document 2), and MMP is also involved in regulation of VEGF or VEGFR2 expression (Non-Patent Documents 3 and 4).
癌の成長、血管新生及び転移の統合された調節は、最終的に、癌を治療し、癌の転移による死亡率を減少させる効率的な方法である。また、癌の成長、血管新生、及び癌細胞浸潤／転移の全過程に関与するＲＴＫのような標的分子を選択することが効率的であろう。さらに、従来の癌成長を抑制する抗癌剤は、長期投与にとよる毒性問題などを引き起こすことから、転移抑制効果があり、毒性の低い有効な抗癌剤である薬剤の開発が必要とされる。 The integrated regulation of cancer growth, angiogenesis and metastasis is ultimately an efficient way to treat cancer and reduce mortality from cancer metastasis. It would also be efficient to select target molecules such as RTKs involved in the whole process of cancer growth, angiogenesis, and cancer cell invasion / metastasis. Furthermore, conventional anti-cancer drugs that suppress cancer growth cause toxicity problems due to long-term administration, and therefore, there is a need to develop drugs that are effective anti-cancer drugs that have metastasis-suppressing effects and low toxicity.
本発明者らは、特定構造を有する７−アザインドリン−２−オン誘導体又はその薬学的に許容される塩が癌の成長抑制剤効果に優れていることを確認し、本発明を完成した。 The present inventors have confirmed that a 7-azaindoline-2-one derivative having a specific structure or a pharmaceutically acceptable salt thereof has an excellent cancer growth inhibitor effect, and completed the present invention.
従って、本発明の目的は、７−アザインドリン−２−オン誘導体又はその薬学的に許容される塩を有効成分として含有する癌疾患の予防又は治療のための医薬組成物を提供するこことである。 Therefore, an object of the present invention is to provide a pharmaceutical composition for preventing or treating a cancer disease, comprising a 7-azaindoline-2-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient. is there.
前記目的を達成するために、本発明は、下記式（１）で示される化合物又はその薬学的許容される塩を提供する：
Ｒ２及びＲ３は、それぞれ独立して、炭素数１〜４のアルキルであり、
Ｒ６は、水素；炭素数１〜１２のアルキル；炭素数２〜１２のアルケニル；炭素数６〜１２のアリール；及びヘテロ原子が１〜３個含まれた炭素数３〜１２のヘテロアリールからなる群から選ばれたいずれか一つであり、
ここで、前記炭素数１〜１２のアルキル又は炭素数２〜１２のアルケニルは、炭素数６〜１２のアリールで置換され又は置換されておらず、
前記炭素数６〜１２のアリールは、ハロゲン；−ＮＯ２；炭素数１〜４のアルキル；−ＯＲ１１；及び−ＮＲ２０Ｒ２１からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
前記炭素数３〜１２のヘテロアリールは、炭素数１〜４のアルキル；−Ｃ（Ｏ）Ｒ１４；−Ｃ（Ｏ）ＯＲ１５；及び−Ｃ（Ｏ）ＮＲ２２Ｒ２３からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
前記Ｒ１１、Ｒ１４及びＲ１５は、それぞれ独立して、水素；及び炭素数１〜４のアルキルからなる群から選ばれたいずれか一つであり、
前記Ｒ２０〜Ｒ２３は、それぞれ独立して、水素；及び炭素数１〜６のアルキルからなる群から選ばれたいずれか一つであるか、又は前記Ｒ２２及びＲ２３は、共にヘテロ原子が１〜３個含まれた炭素数３〜８のヘテロアリールを形成してもよく、
ここで、Ｒ１１、Ｒ１４、Ｒ１５、及びＲ２０〜Ｒ２３の炭素数１〜４のアルキル；及び炭素数３〜８のヘテロアリールは、それぞれ独立して、炭素数１〜４のアルキル；及び−ＮＲ２４Ｒ２５からなる群から選ばれたどれか一つ以上の置換基で置換され又は置換されておらず、
Ｒ２４及びＲ２５は、それぞれ独立して、水素；及び炭素数１〜４のアルキルからなる群から選ばれたいずれか一つであるか、又はＲ２４及びＲ２５は、共にヘテロ原子が１〜３個含まれた炭素数３〜８のヘテロアリールを形成してもよい。］
In order to achieve the above object, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
R 2 and R 3 are each independently alkyl having 1 to 4 carbons;
R 6 is hydrogen; alkyl having 1 to 12 carbons; alkenyl having 2 to 12 carbons; aryl having 6 to 12 carbons; and heteroaryl having 3 to 12 carbons containing 1 to 3 heteroatoms. One of the group
Here, the alkyl having 1 to 12 carbons or the alkenyl having 2 to 12 carbons is substituted or unsubstituted with aryl having 6 to 12 carbons,
The aryl having 6 to 12 carbon atoms is substituted with one or more substituents selected from the group consisting of halogen; -NO 2 ; alkyl having 1 to 4 carbon atoms; -OR 11 ; and -NR 20 R 21. Or not replaced,
Heteroaryl of said 3 to 12 carbon atoms, alkyl of 1 to 4 carbon atoms; selected from the group consisting of and -C (O) NR 22 R 23 ; -C (O) R 14; -C (O) OR 15 Substituted or unsubstituted with one or more substituents
R 11 , R 14 and R 15 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 4 carbon atoms;
Wherein R 20 to R 23 are each independently hydrogen; and either any one selected from the group consisting of alkyl having 1 to 6 carbon atoms, or said R 22 and R 23 are both heteroatoms May form a heteroaryl having 3 to 8 carbon atoms containing 1 to 3 carbon atoms,
Here, R 11 , R 14 , R 15 , and R 20 to R 23 alkyl having 1 to 4 carbon atoms; and heteroaryl having 3 to 8 carbon atoms are each independently an alkyl having 1 to 4 carbon atoms. And substituted or unsubstituted with any one or more substituents selected from the group consisting of -NR 24 R 25 ;
R 24 and R 25 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 4 carbon atoms, or R 24 and R 25 each have 1 heteroatom. Heteroaryl having from 3 to 3 carbon atoms may be formed. ]
また、本発明は、下記式（２）の化合物と下記式（３）の化合物とを反応させて、下記式（１）の化合物を製造する方法を提供する：
また、本発明は、前記化合物又はその薬学的に許容される塩を有効成分として含む癌疾患予防又は治療用医薬組成物を提供する。 The present invention also provides a pharmaceutical composition for preventing or treating cancer diseases, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
さらに、本発明は、前記化合物又はその薬学的に許容される塩を有効成分として含む癌浸潤又は癌転移予防又は抑制用医薬組成物を提供する。 Further, the present invention provides a pharmaceutical composition for preventing or inhibiting cancer invasion or metastasis, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
本発明に係る７−アザインドリン−２−オン誘導体又はその薬学的許容される塩は、癌成長抑制剤及び癌転移抑制用薬剤として好適に用いることができる。 The 7-azaindoline-2-one derivative or a pharmaceutically acceptable salt thereof according to the present invention can be suitably used as a cancer growth inhibitor and a cancer metastasis inhibitor.
以下、本発明の構成を具体的に説明する。 Hereinafter, the configuration of the present invention will be specifically described.
本発明は、下記式（１）で示される化合物（以下、‘式（１）の化合物’）又はその薬学的に許容される塩を提供する：
Ｒ２及びＲ３は、それぞれ独立して、炭素数１〜４のアルキルであり、
Ｒ６は、水素；炭素数１〜１２のアルキル；炭素数２〜１２のアルケニル；炭素数６〜１２のアリール；及びヘテロ原子が１〜３個含まれた炭素数３〜１２のヘテロアリールからなる群から選ばれたいずれか一つであり、
ここで、前記炭素数１〜１２のアルキル又は炭素数２〜１２のアルケニルは、炭素数６〜１２のアリールで置換され又は置換されておらず、
前記炭素数６〜１２のアリールは、ハロゲン；−ＮＯ２；炭素数１〜４のアルキル；−ＯＲ１１；及び−ＮＲ２０Ｒ２１からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
前記炭素数３〜１２のヘテロアリールは、炭素数１〜４のアルキル；−Ｃ（Ｏ）Ｒ１４；−Ｃ（Ｏ）ＯＲ１５；及び−Ｃ（Ｏ）ＮＲ２２Ｒ２３からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
前記Ｒ１１、Ｒ１４及びＲ１５は、それぞれ独立して、水素；及び炭素数１〜４のアルキルからなる群から選ばれたいずれか一つであり、
前記Ｒ２０〜Ｒ２３は、それぞれ独立して、水素；及び炭素数１〜６のアルキルからなる群から選ばれたいずれか一つであるか、又は前記Ｒ２２及びＲ２３は、共にヘテロ原子が１〜３個含まれた炭素数３〜８のヘテロアリールを形成してもよく、
ここで、Ｒ１１、Ｒ１４、Ｒ１５、及びＲ２０〜Ｒ２３の炭素数１〜４のアルキル；及び炭素数３〜８のヘテロアリールは、それぞれ独立して、炭素数１〜４のアルキル；及び−ＮＲ２４Ｒ２５からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
Ｒ２４及びＲ２５は、それぞれ独立して、水素；及び炭素数１〜４のアルキルからなる群から選ばれたいずれか一つであるか、又はＲ２４及びＲ２５は、共にヘテロ原子が１〜３個含まれた炭素数３〜８のヘテロアリールを形成してもよい。］
The present invention provides a compound represented by the following formula (1) (hereinafter, 'compound of formula (1)') or a pharmaceutically acceptable salt thereof:
R 2 and R 3 are each independently alkyl having 1 to 4 carbons;
R 6 is hydrogen; alkyl having 1 to 12 carbons; alkenyl having 2 to 12 carbons; aryl having 6 to 12 carbons; and heteroaryl having 3 to 12 carbons containing 1 to 3 heteroatoms. One of the group
Here, the alkyl having 1 to 12 carbons or the alkenyl having 2 to 12 carbons is substituted or unsubstituted with aryl having 6 to 12 carbons,
The aryl having 6 to 12 carbon atoms is substituted with one or more substituents selected from the group consisting of halogen; -NO 2 ; alkyl having 1 to 4 carbon atoms; -OR 11 ; and -NR 20 R 21. Or not replaced,
Heteroaryl of said 3 to 12 carbon atoms, alkyl of 1 to 4 carbon atoms; selected from the group consisting of and -C (O) NR 22 R 23 ; -C (O) R 14; -C (O) OR 15 Substituted or unsubstituted with one or more substituents
R 11 , R 14 and R 15 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 4 carbon atoms;
Wherein R 20 to R 23 are each independently hydrogen; and either any one selected from the group consisting of alkyl having 1 to 6 carbon atoms, or said R 22 and R 23 are both heteroatoms May form a heteroaryl having 3 to 8 carbon atoms containing 1 to 3 carbon atoms,
Here, R 11 , R 14 , R 15 , and R 20 to R 23 alkyl having 1 to 4 carbon atoms; and heteroaryl having 3 to 8 carbon atoms are each independently an alkyl having 1 to 4 carbon atoms. And substituted or unsubstituted with one or more substituents selected from the group consisting of -NR 24 R 25 ;
R 24 and R 25 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 4 carbon atoms, or R 24 and R 25 each have 1 heteroatom. Heteroaryl having from 3 to 3 carbon atoms may be formed. ]
本発明において、前記式（１）の化合物は、７−アザインドリン−２−オン誘導体と称することがある。 In the present invention, the compound of the formula (1) may be referred to as a 7-azaindoline-2-one derivative.
また、本発明の化合物の置換基の定義に使用された用語は以下の通りである。 The terms used to define the substituents of the compound of the present invention are as follows.
特に明記しない限り、用語「アルキル」は、示された数の炭素原子を有する直鎖又は分岐鎖又は環状の飽和炭化水素を指す。 Unless otherwise specified, the term "alkyl" refers to a straight or branched or cyclic saturated hydrocarbon having the indicated number of carbon atoms.
特に明記しない限り、用語「アルケニル」は、示された数の炭素原子、少なくとも二つの炭素原子及び少なくとも一つの炭素−炭素二重結合を有する炭化水素を指す。 Unless otherwise specified, the term "alkenyl" refers to a hydrocarbon having the indicated number of carbon atoms, at least two carbon atoms, and at least one carbon-carbon double bond.
用語「ハロゲン」は、フルオロ（Ｆ）、クロロ（Ｃｌ）、ブロモ（Ｂｒ）又はヨード（Ｉ）を指す。 The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).
特に明記しない限り、用語「複素環」は、酸素（O）、窒素（Ｎ）及び硫黄（Ｓ）のヘテロ原子を含む非芳香族飽和炭化水素環、又は芳香環として単環及び縮合環を意味する。 Unless otherwise specified, the term “heterocycle” means a non-aromatic saturated hydrocarbon ring containing oxygen (O), nitrogen (N) and sulfur (S) heteroatoms, or a single ring and a condensed ring as an aromatic ring. I do.
特に明記しない限り、用語「アリール」は、５員及び６員の単環式芳香族基を含む１価及び２価の芳香族基を指す。 Unless otherwise specified, the term "aryl" refers to monovalent and divalent aromatic groups, including 5- and 6-membered monocyclic aromatic groups.
用語「ヘテロアリール」は、窒素（Ｎ）、酸素（Ｏ）及び硫黄（S）から独立して選ばれる１〜３個のヘテロ原子を含有する５員及び６員の単環式芳香族基を含む１価及び２価の芳香族基を指す。ヘテロアリールの例は、フラニル、ピロリル、チオフェニル、チアゾリル、イソチアゾリル、イミダゾリル、トリアゾリル、テトラゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、ピリジニル、ピラジニル、ピリダジニル、ピリミジニル、イソキノリニル、カルバゾリル、ベンゾオキサゾリル、ベンゾジオキサゾリル、ベンゾチアゾリル、ベンゾイミダゾリル、ベンゾチオフェニル、トリアジニル、フタラジニル、キノリニル、インドリル、ベンゾフラニル、プリニル及びインドリジニルが挙げられるが、これらに制限されない。 The term "heteroaryl" refers to 5- and 6-membered monocyclic aromatic groups containing from 1 to 3 heteroatoms independently selected from nitrogen (N), oxygen (O) and sulfur (S). And monovalent and divalent aromatic groups. Examples of heteroaryl are furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, carbazolyl, benzoxazolyl, benzodioxazolyl Benzothiazolyl, benzimidazolyl, benzothiophenyl, triazinyl, phthalazinyl, quinolinyl, indolyl, benzofuranyl, prenyl and indolizinyl.
用語「医薬組成物」は、本発明による化合物又はその生理学的／薬学的に許容される塩又はそのプロドラックと、生理学的／薬学的に許容される担体及び賦形剤などの他の化学成分との混合物を指す。 The term “pharmaceutical composition” refers to a compound according to the invention or a physiological / pharmaceutically acceptable salt thereof or a prodrug thereof and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. Refers to a mixture with
また、式（１）の化合物は、プロドラッグとして作用し得る。用語「プロドラッグ」は、体内で親薬物に変換される物質を指す。プロドラッグは、親薬物よりも投与が容易なことがあるため、しばしば有用である。例えば、親薬物が経口投与時、生体利用可能（bioavailable）でなくても、そのプロドラッグは、経口投与時、生体利用可能であり得る。さらに、プロドラッグは、医薬組成物中の親薬物と比較して改善された溶解度を示すことができる。 Also, the compound of formula (1) can act as a prodrug. The term "prodrug" refers to a substance that is converted into the parent drug in the body. Prodrugs are often useful because they may be easier to administer than the parent drug. For example, a prodrug may be bioavailable upon oral administration even though the parent drug is not bioavailable upon oral administration. In addition, prodrugs can exhibit improved solubility as compared to the parent drug in a pharmaceutical composition.
用語「生理的／薬学的に許容される担体」は、生物に有意な刺激を引き起こさず、投与された化合物の生物学的活性及び特性を除去しない担体又は希釈剤を指す。 The term "physiologically / pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
用語「生理的／薬学的に許容される賦形剤」は、活性成分の投与をさらに容易にするために医薬組成物に添加される不活性物質を指す。賦形剤の例には、炭酸カルシウム、リン酸カルシウム、多様な糖及びデンプンの種類、セルロース誘導体、ゼラチン、植物油及びポリエチレングリコールをなどが挙げられるが、これらに制限されない。 The term "physiologically / pharmaceutically acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugar and starch types, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and the like.
用語「治療する、「治療すること」及び「治療」は、本発明による疾患又はそれに関連する症状を軽減又は除去する方法を指す。特に癌に関して、これらの用語は、癌に罹患している個体の生残率を増加させこと、又は疾患の一つ以上の症状を軽減することを単に意味する。 The terms "treat," "treating" and "treatment" refer to a method of alleviating or eliminating a disease or a symptom associated therewith according to the present invention. Particularly with respect to cancer, these terms simply mean increasing the survival of the individual suffering from the cancer, or reducing one or more symptoms of the disease.
用語「生物体」は、少なくとも一つ以上の細胞で構成された全ての生物を意味する。生きている生物体は、真核生物の単細胞と同じくらい単純なものでも、ヒトを含む哺乳動物ほど複雑なものであってもよい。 The term "organism" refers to any organism made up of at least one or more cells. Living organisms can be as simple as a single eukaryotic cell or as complex as a mammal, including a human.
用語「治療有効量」は、治療される疾患の一つ以上の症状をある程度軽減させることができる化合物の量を指す。癌の治療に関して、治療有効量は、以下の効果を有する量を指す：
（１）腫瘍サイズの減少；
（２）腫瘍の転移抑制（即ち、ある程度減速させ、好ましくは中断させる）；
（３）腫瘍の成長をある程度抑制（すなわち、ある程度減速させ、好ましくは中断させる）；及び／又は
（４）癌に関連した一つ以上の症状をある程度軽減（又は、好ましくは除去）。
The term "therapeutically effective amount" refers to an amount of a compound that is capable of alleviating one or more symptoms of the disease being treated. For the treatment of cancer, a therapeutically effective amount refers to an amount that has the following effects:
(1) decrease in tumor size;
(2) inhibiting metastasis of the tumor (ie, slowing down to some extent, preferably interrupting);
(3) to some extent inhibit (ie, to some extent slow down, and preferably to interrupt) tumor growth; and / or (4) to alleviate (or preferably eliminate) one or more symptoms associated with cancer.
本発明の一実施形態において、式（１）の化合物のＲ１、Ｒ４及びＲ５は、水素であり、Ｒ２及びＲ３はメチルであってもよい。 In one embodiment of the present invention, R 1 , R 4 and R 5 of the compound of formula (1) are hydrogen and R 2 and R 3 may be methyl.
また、一実施形態において、式（１）の化合物のＲ６は、
水素；
ＯＨ及びメトキシからなる群から選ばれた一つ以上の置換基で置換された又は置換されていない炭素数６〜１２のアリールで置換された又は置換されていない炭素数１〜１２のアルキル又は炭素数２〜１２のアルケニル；
ハロゲン、−ＮＯ２、ＯＨ、メトキシ、メチル、エチル、プロピル、メチルアミン、エチルアミン、ジメチルアミン及びジエチルアミンからなる群から選ばれた一つ以上の置換基で置換された又は置換されていない炭素数６〜１２のアリール；又は
メチル；エチル；−Ｃ（Ｏ）ＯＲ１５；及び−Ｃ（Ｏ）ＮＲ２２Ｒ２３からなる群から選ばれた一つ以上の置換基で置換された又は置換されていないヘテロ原子が１〜３個含まれた炭素数３〜１２のヘテロアリールを表し、
前記Ｒ１５は、水素、メチル又はエチルを表し、
前記Ｒ２２及びＲ２３は、それぞれ独立して、水素；又はメチルアミン、エチルアミン、ジメチルアミン、ジエチルアミン及びピペリジンからなる群から選ばれた一つ以上の置換基で置換された又は置換されていないメチル又はエチルを表すか、又は 前記Ｒ２２及びＲ２３は、共にメチルで置換された又は置換されていないシクロヘキサン、ピペラジン、ピペリジン、ピロリジン、又はモルホリンを形成してもよい。
Also, in one embodiment, R 6 of the compound of formula (1) is
hydrogen;
Alkyl or carbon having 1 to 12 carbon atoms substituted or unsubstituted with aryl having 6 to 12 carbon atoms substituted or unsubstituted with one or more substituents selected from the group consisting of OH and methoxy Alkenyl of the formulas 2 to 12;
Halogen, -NO 2, OH, methoxy, methyl, ethyl, propyl, methylamine, ethylamine, carbon atoms not been or substituted substituted by one or more substituents selected from the group consisting of dimethylamine and diethylamine 6 -C (O) OR < 15 >; and -C (O) NR < 22 > R < 23 > substituted or unsubstituted with one or more substituents selected from the group consisting of: Represents a heteroaryl having 3 to 12 carbon atoms containing 1 to 3 hetero atoms,
R 15 represents hydrogen, methyl or ethyl;
R 22 and R 23 each independently represent hydrogen; or methyl substituted or unsubstituted with one or more substituents selected from the group consisting of methylamine, ethylamine, dimethylamine, diethylamine and piperidine. Or R 22 and R 23 may form cyclohexane, piperazine, piperidine, pyrrolidine, or morpholine, both substituted or unsubstituted with methyl.
また、一実施形態において、式（１）の化合物のＲ６は、
一つ以上のフェニルで置換された又は置換されていない炭素数１〜８のアルキル；
ＯＨ及びメトキシからなる群から選ばれた一つ以上の置換基で置換された又は置換されていないフェニルで置換された又は置換されていない炭素数２〜８のアルケニル；
ハロゲン、−ＮＯ２、ＯＨ、メトキシ、メチル、エチル、ジメチルアミン、ジエチルアミンからなる群から選ばれた一つ以上の置換基で置換された又は置換されていない炭素数６〜１０のアリール；又は
メチル；エチル；−Ｃ（Ｏ）ＯＲ１５；及び−Ｃ（Ｏ）ＮＲ２２Ｒ２３からなる群から選ばれた一つ以上の置換基で置換された又は置換されていない、ヘテロ原子が１〜３個含まれた炭素数３〜１０のヘテロアリールを表し、
前記Ｒ１５は、水素、メチル又はエチルを表し、
前記Ｒ２２及びＲ２３は、それぞれ独立して、水素；又はメチルアミン、エチルアミン、ジメチルアミン、ジエチルアミン及びピペリジンからなる群から選ばれた一つ以上の置換基で置換された又は置換されていないメチル又はエチルを表すか、又は
前記Ｒ２２及びＲ２３は、共にメチルで置換された又は置換されていないシクロヘキサン、ピペラジン、ピペリジン、ピロリジン、又はモルホリンを形成してもよい。
Also, in one embodiment, R 6 of the compound of formula (1) is
C1-C8 alkyl substituted or unsubstituted with one or more phenyl;
C2-C8 alkenyl substituted or unsubstituted with phenyl substituted or unsubstituted with one or more substituents selected from the group consisting of OH and methoxy;
Halogen, -NO 2, OH, methoxy, methyl, ethyl, dimethylamine, having 6 to 10 carbon atoms that are not the or substituted substituted by one or more substituents selected from the group consisting of diethylamine aryl; or methyl Ethyl; —C (O) OR 15 ; and —C (O) NR 22 R 23 , wherein the heteroatom is substituted or unsubstituted with one or more substituents selected from the group consisting of 1 to 3; Represents a heteroaryl having 3 to 10 carbon atoms,
R 15 represents hydrogen, methyl or ethyl;
R 22 and R 23 each independently represent hydrogen; or methyl substituted or unsubstituted with one or more substituents selected from the group consisting of methylamine, ethylamine, dimethylamine, diethylamine and piperidine. Or R 22 and R 23 may form cyclohexane, piperazine, piperidine, pyrrolidine, or morpholine, both substituted or unsubstituted with methyl.
より具体的に、本発明の式（１）の化合物は、３−アルキリデン−５−ヒドロキシ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン誘導体であってもよい。 More specifically, the compound of formula (1) of the present invention may be a 3-alkylidene-5-hydroxy-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one derivative.
前記誘導体は、下記表１のように式（Ｉ−０１）〜（Ｉ−４６）で示される化合物からなる群から選ばれたいずれか一つであってもよい。
本発明において、薬学的に許容される塩は、シュウ酸、マレイン酸、フマル酸、リンゴ酸、酒石酸、クエン酸及び安息香酸からなる群から選ばれた有機酸、又は塩酸、硫酸、リン酸及び臭化水素酸からなる群から選ばれた無機酸によって形成される酸付加塩の形態であってもよい。 In the present invention, the pharmaceutically acceptable salt is oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, organic acid selected from the group consisting of citric acid and benzoic acid, or hydrochloric acid, sulfuric acid, phosphoric acid and It may be in the form of an acid addition salt formed by an inorganic acid selected from the group consisting of hydrobromic acid.
また、本発明は式（１）の化合物を製造する方法を提供する。前記製造は、例えば、下記式（２）の化合物と下記式（３）の化合物を反応させて、下記式（１）の化合物を製造することができる：
Ｒ２及びＲ３は、それぞれ独立して、炭素数１〜４のアルキルであり、
Ｒ６は、水素；炭素数１〜１２のアルキル；炭素数２〜１２のアルケニル；炭素数６〜１２のアリール；及びヘテロ原子が１〜３個含まれた炭素数３〜１２のヘテロアリールからなる群から選ばれたいずれか一つであり、
ここで、前記炭素数１〜１２のアルキル又は炭素数２〜１２のアルケニルは、炭素数６〜１２のアリールで置換され又は置換されておらず、
前記炭素数６〜１２のアリールは、ハロゲン；−ＮＯ２；炭素数１〜４のアルキル；−ＯＲ１１；及び−ＮＲ２０Ｒ２１からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
前記炭素数３〜１２のヘテロアリールは、炭素数１〜４のアルキル；−Ｃ（Ｏ）Ｒ１４；−Ｃ（Ｏ）ＯＲ１５；及び−Ｃ（Ｏ）ＮＲ２２Ｒ２３からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
前記Ｒ１１、Ｒ１４及びＲ１５は、それぞれ独立して、水素；及び炭素数１〜４のアルキルからなる群から選ばれたいずれか一つであり、
前記Ｒ２０〜Ｒ２３は、それぞれ独立して、水素；及び炭素数１〜６のアルキルからなる群から選ばれたいずれか一つであるか、又は前記Ｒ２２及びＲ２３は、共にヘテロ原子が１〜３個含まれた炭素数３〜８のヘテロアリールを形成してもよく、
ここで、Ｒ１１、Ｒ１４、Ｒ１５、及びＲ２０〜Ｒ２３の炭素数１〜４のアルキル；及び炭素数３〜８のヘテロアリールは、それぞれ独立して、炭素数１〜４のアルキル；及び−ＮＲ２４Ｒ２５からなる群から選ばれたどれか一つ以上の置換基で置換され又は置換されておらず、
Ｒ２４及びＲ２５は、それぞれ独立して、水素；及び炭素数１〜４のアルキルからなる群から選ばれたいずれか一つであるか、又はＲ２４及びＲ２５は、共にヘテロ原子が１〜３個含まれた炭素数３〜８のヘテロアリールを形成してもよい。］
The present invention also provides a method for producing the compound of the formula (1). In the above production, for example, a compound of the following formula (1) can be prepared by reacting a compound of the following formula (2) with a compound of the following formula (3):
R 2 and R 3 are each independently alkyl having 1 to 4 carbons;
R 6 is hydrogen; alkyl having 1 to 12 carbons; alkenyl having 2 to 12 carbons; aryl having 6 to 12 carbons; and heteroaryl having 3 to 12 carbons containing 1 to 3 heteroatoms. One of the group
Here, the alkyl having 1 to 12 carbons or the alkenyl having 2 to 12 carbons is substituted or unsubstituted with aryl having 6 to 12 carbons,
The aryl having 6 to 12 carbon atoms is substituted with one or more substituents selected from the group consisting of halogen; -NO 2 ; alkyl having 1 to 4 carbon atoms; -OR 11 ; and -NR 20 R 21. Or not replaced,
Heteroaryl of said 3 to 12 carbon atoms, alkyl of 1 to 4 carbon atoms; selected from the group consisting of and -C (O) NR 22 R 23 ; -C (O) R 14; -C (O) OR 15 Substituted or unsubstituted with one or more substituents
R 11 , R 14 and R 15 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 4 carbon atoms;
Wherein R 20 to R 23 are each independently hydrogen; and either any one selected from the group consisting of alkyl having 1 to 6 carbon atoms, or said R 22 and R 23 are both heteroatoms May form a heteroaryl having 3 to 8 carbon atoms containing 1 to 3 carbon atoms,
Here, R 11 , R 14 , R 15 , and R 20 to R 23 alkyl having 1 to 4 carbon atoms; and heteroaryl having 3 to 8 carbon atoms are each independently an alkyl having 1 to 4 carbon atoms. And substituted or unsubstituted with any one or more substituents selected from the group consisting of -NR 24 R 25 ;
R 24 and R 25 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 4 carbon atoms, or R 24 and R 25 each have 1 heteroatom. Heteroaryl having from 3 to 3 carbon atoms may be formed. ]
一実施形態において、前記式（１）の化合物は、下記の反応スキーム（１）のような製造方法によって製造されることができる：
＜反応スキーム１＞
<Reaction Scheme 1>
また、本発明は、前記式（１）で示される化合物又はその薬学的に許容される塩を有効成分として含有する癌疾患予防又は治療用医薬組成物を提供する。
また、前述した式（１）で示される化合物又はその薬学的に許容される塩を有効成分として含有する癌浸潤又は癌転移予防又は抑制用医薬組成物を提供する。
The present invention also provides a pharmaceutical composition for preventing or treating a cancer disease, comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also provides a pharmaceutical composition for preventing or suppressing cancer invasion or metastasis, comprising a compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
前記癌は、肺癌、乳癌、膀胱癌、骨癌、甲状腺癌、副甲状腺癌、直膓癌、前立腺癌、腎臓癌、咽喉癌、喉頭癌、食道癌、膵臓癌、大腸癌、胃癌、舌癌、皮膚癌、脳腫瘍、子宮癌、頭部又は頸部癌、胆のう癌、口腔癌、結腸癌、肛門癌、中枢神経系腫瘍及び肝癌からなる群から選ばれたいずれか一つであってもよい。 The cancer is lung cancer, breast cancer, bladder cancer, bone cancer, thyroid cancer, parathyroid cancer, colon cancer, prostate cancer, kidney cancer, throat cancer, larynx cancer, esophageal cancer, pancreatic cancer, colon cancer, stomach cancer, tongue cancer May be any one selected from the group consisting of skin cancer, brain tumor, uterine cancer, head or neck cancer, gall bladder cancer, oral cancer, colon cancer, anal cancer, central nervous system tumor and liver cancer. .
本発明による式（１）の化合物又はその薬学的に許容される塩は、患者にそのまま投与することができ、又は化合物を適当な担体又は賦形剤と混合した医薬組成物で投与することができる。薬物の製剤と投与の技術は、「Remington’s Pharmacological Sciences,」Mack Publishing Co., Easton, PA.,最新版から見出せる。 The compound of formula (1) or a pharmaceutically acceptable salt thereof according to the present invention can be administered to the patient as is, or can be administered in a pharmaceutical composition in which the compound is mixed with a suitable carrier or excipient. it can. Techniques for drug formulation and administration can be found in "Remington's Pharmacological Sciences," Mack Publishing Co., Easton, PA., Latest edition.
前記文献によれば、「投与」又は「投与する」は、前記疾患の治療又は予防のために、式（１）の化合物又はその薬学的に許容される塩又は式（１）の化合物を含む医薬組成物を生物体に伝達することを指す。 According to the literature, "administration" or "administering" includes a compound of formula (1) or a pharmaceutically acceptable salt thereof or a compound of formula (1) for the treatment or prevention of the disease. Refers to delivering a pharmaceutical composition to an organism.
好適な投与経路は、経口、直腸、粘膜又は腸管投与又は筋肉内、皮下、髄内、髄腔内、直接的な心室内、血管内、硝子体内、腹膜内、鼻腔内、又は眼内注射などであってもよい。前記投与の好ましい経路は、経口及び非経口投与であってもよい。 Suitable routes of administration include oral, rectal, mucosal or intestinal administration or intramuscular, subcutaneous, intramedullary, intrathecal, direct intraventricular, intravascular, intravitreal, intraperitoneal, intranasal, or intraocular injection, etc. It may be. Preferred routes of administration may be oral and parenteral.
代替的に、化合物は、全身投与によってではなく、例えば、固形癌への化合物の直接投与を介して、しばしば、デポー（depo）製剤又は徐放性製剤中で、局所投与することができる。 Alternatively, the compounds can be administered topically, rather than by systemic administration, for example, via direct administration of the compound to a solid cancer, often in a depot or sustained release formulation.
また、腫瘍特異的抗体で被覆されたリポソームなどの標的薬物送達システムで薬物を投与することができる。リポソームは、腫瘍を標的として、腫瘍によって選択的に取り込まれ得る。 Also, the drug can be administered in a targeted drug delivery system such as a liposome coated with a tumor-specific antibody. Liposomes can target a tumor and be selectively taken up by the tumor.
本発明の医薬組成物は、この分野における通常の混合、溶解、顆粒化、糖衣錠化、粉末化（levigating）、乳剤化、カプセル化、封入と凍結乾燥工程などの良く知られた工程で製造することができる。 The pharmaceutical compositions of the present invention are manufactured by well-known processes such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating and lyophilizing steps which are common in this field. be able to.
本発明による医薬組成物は、活性化合物を薬学的に使用できる製剤に製剤化することができる。適した製剤は、投与経路の選択に応じて変化し得る。 The pharmaceutical composition according to the present invention can be formulated into a pharmaceutically usable formulation of the active compound. Suitable formulations can vary depending on the choice of the route of administration.
注射のために、本発明の化合物は、水溶液、好ましくはハンクス溶液（Hank's solution）、リンゲル液又は生理食塩水のような生理学的に適した緩衝液に製剤化することができる。 For injection, the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically suitable buffers such as Hank's solution, Ringer's solution, or physiological saline.
鼻点膜投与するために、薬剤を障壁に浸透させる浸透剤を製剤に使用することができる。当該技術分野で一般的に知られている浸透剤を使用することができる。 For nasal administration, penetrants that allow the agent to penetrate the barrier can be used in the formulation. Penetrants commonly known in the art can be used.
経口投与のために、化合物は、薬学的に許容される担体と組み合わせることによって製剤化することができる。このような担体は、患者による経口摂取のために、本発明の化合物を錠剤、丸剤、トローチ剤（lozenge）、糖衣錠、カプセル、液体、ゲル、シロップ、スラリー（slurries）、懸濁液などとして製剤化することができる。経口投与のための薬学製剤は、錠剤又は糖衣錠のコアを製造するために、必要に応じて他の適当な補助剤を添加した後、固形賦形剤を使用して製造することができる。必要に応じて、得られた混合物を粉砕し、顆粒を製造するために加工してもよい。有用な賦形剤は、ラクトース、スクロース、マンニトール又はソルビトールを含む糖類；トウモロコシデンプン、小麦デンプン、米デンプンとジャガイモデンプンのような繊維質製剤；ゼラチン、ガム類、ゴム樹液、メチルセルロース、ヒドロキシプロピルメチル−セルロース、及び/又はポリビニル−ピロリドン（ＰＶＰ）などの充填剤が挙げられる。必要であれば、架橋ポリビニル−ピロリドン、寒天又はアルギン酸のような崩壊剤を添加することもできる。また、アルギン酸ナトリウムのような塩を添加することもできる。 For oral administration, the compounds can be formulated by combining with a pharmaceutically acceptable carrier. Such carriers enable the compounds of the present invention to be administered as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. It can be formulated. Pharmaceutical preparations for oral administration can be prepared using solid excipients, if desired, after adding other suitable auxiliaries to produce tablets or dragee cores. If necessary, the resulting mixture may be milled and processed to produce granules. Useful excipients are sugars including lactose, sucrose, mannitol or sorbitol; fibrous preparations such as corn starch, wheat starch, rice starch and potato starch; gelatin, gums, gum sap, methylcellulose, hydroxypropylmethyl- Fillers such as cellulose and / or polyvinyl-pyrrolidone (PVP) are included. If desired, disintegrating agents may be added, such as the cross-linked polyvinyl-pyrrolidone, agar, or alginic acid. Also, salts such as sodium alginate can be added.
糖衣錠のコアは、適切にコーティングして製造することができる。このために、選択的に、アラビアガム、ポリビニルピロリドン、カーボポールゲル、ポリエチレングリコール及び／又は二酸化チタン、ラッカー溶液を含有する濃縮した糖溶液を使用することができる。 Dragee cores can be made with suitable coatings. For this purpose, it is optionally possible to use a concentrated sugar solution containing gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, a lacquer solution.
経口的に使用できる医薬組成物は、ゼラチンとクルリセロラナソルビトールのような可塑剤で製造した軟質密封カプセルだけでなく、ゼラチンで製造した押し込み式カプセルを含むことができる。軟質カプセルにおいて、活性化合物は、脂肪油、流動パラフィンや液体ポリエチレングリコールなどの適切な溶液に溶解又は懸濁されてもよい。また、安定剤を組成物中に添加することができる。 Pharmaceutical compositions that can be used orally can include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as clurycellona sorbitol. In soft capsules, the active compounds may be dissolved or suspended in suitable solutions, such as fatty oils, liquid paraffin or liquid polyethylene glycol. Also, stabilizers can be added to the composition.
使用することができる医薬組成物には、硬質ゼラチンカプセルを含むことができる。 Pharmaceutical compositions that can be used can include hard gelatin capsules.
カプセルは、活性成分を光から活性化合物を保護するために、茶色ガラス又はプラスチックボトルに充填さてもよい。活性化合物カプセル製剤を入れた容器は、制御された室温（１５〜３０℃）で保管することができる。 Capsules may be filled into brown glass or plastic bottles to protect the active ingredient from light. Containers containing the active compound capsule formulation can be stored at a controlled room temperature (15-30 ° C).
吸入による投与のために、本発明による化合物は、圧縮容器、ネブライザー（nebulizer）及びジクロロジフルオロメタン、トリクロロフルオロメタン、ジクロロテトラ−フルオロエタン及び二酸化炭素のような適切な噴射剤を使用してエアゾールスプレーの形態で容易に投与さすることができる。 For administration by inhalation, the compounds according to the invention can be prepared by means of an aerosol spray using a compressed container, a nebulizer and a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane and carbon dioxide. It can be easily administered in the form of
また、化合物は、例えば、ボーラス注入又は持続静脈注射により非経口的に投与するように製剤化することができる。注入するための製剤は、例えば、アンプル又は多用量容器のような保存剤が添加された単位剤形で提供することができる。組成物は、油性又は水性ビヒクル中の懸濁液、溶液又はエマルションの形態をとり、懸濁剤、安定化剤及び／又は分散剤のような製剤化物質を含むことができる。 The compounds can also be formulated for parenteral administration, for example, by bolus injection or continuous intravenous injection. Formulations for injection may be presented in unit dosage form with an added preservative such as, for example, an ampoule or a multi-dose container. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.
非経口投与のための医薬組成物は、水溶性形態の水溶液、例えば、水溶性形態の活性化合物の水溶液、例えば、塩を含む。また、活性化合物の懸濁液は、親油性ビヒクル中で調製することができる。適切な親油性ビヒクルとしては、脂肪油、オレイン酸エチル及びトリグリセリドなどの合成脂肪酸エステル、リポソーム等の物質が挙げられる。水性注射懸濁液は、ナトリウムカルボキシメチルセルロース、ソルビトール又はデキストランのような、懸濁液の粘度を増加させる物質を含有することができる。また、選択的に、懸濁液は適切な安定剤及び／又は化合物の溶解度を高めて高濃度の溶液の調製を可能にする物質を含有することができる。 Pharmaceutical compositions for parenteral administration include aqueous solutions in water-soluble form, for example, aqueous solutions of the active compounds in water-soluble form, for example, salts. Additionally, suspensions of the active compounds may be prepared in lipophilic vehicles. Suitable lipophilic vehicles include fatty oils, synthetic fatty acid esters such as ethyl oleate and triglycerides, and substances such as liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Alternatively, the suspension may also contain suitable stabilizers and / or substances that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
また、化合物は、ココアバター又は他のグリセリドなどの従来の坐薬基剤を用いて、停留浣腸剤のような直腸投与化合物で坐剤に製剤化することができる。 The compounds can also be formulated in suppositories, with rectal compounds such as retention enemas, using conventional suppository bases such as cocoa butter or other glycerides.
また、前記製剤に加えて、化合物は、デポー（depot）製剤として製剤化することができる。このような長時間作用性製剤は、移植（例えば、皮下又は筋肉内）又は筋肉内注射により投与することができる。本発明の化合物は、適切な重合性又は疏水性物質（例えば、薬学的に許容される油を含むエマルション中）、イオン交換樹脂又は難溶性の塩（これに限定されない。）などの難溶性誘導体でこのような経路の投与のために製剤化することができる。 Also, in addition to the formulations, the compounds can be formulated as a depot formulation. Such long acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. The compounds of the present invention can be any suitable polymerizable or hydrophobic material (eg, in an emulsion containing a pharmaceutically acceptable oil), an ion exchange resin, or a sparingly soluble derivative such as, but not limited to, a sparingly soluble salt. Can be formulated for administration by such routes.
本発明による医薬組成物は、前記疾患、例えば、肺癌、乳癌、膀胱癌、骨癌、甲状腺癌、副甲状腺癌、直膓癌、前立腺癌、腎臓癌、咽喉癌、喉頭癌、食道癌、膵臓癌、大腸癌、胃癌、舌癌、皮膚癌、脳腫瘍、子宮癌、頭部又は頸部癌、胆のう癌、口腔癌、結腸癌、肛門癌、中枢神経系腫瘍及び肝癌からなる群から選ばれたどれか一つの疾患の予防又は治療のような意図された目的を達成するのに十分な量の活性化合物が含まれた組成物を意味する。 The pharmaceutical composition according to the present invention may be used for the above-mentioned diseases, for example, lung cancer, breast cancer, bladder cancer, bone cancer, thyroid cancer, parathyroid cancer, colon cancer, prostate cancer, kidney cancer, throat cancer, laryngeal cancer, esophageal cancer, pancreas. Selected from the group consisting of cancer, colorectal cancer, gastric cancer, tongue cancer, skin cancer, brain tumor, uterine cancer, head or neck cancer, gallbladder cancer, oral cancer, colon cancer, anal cancer, central nervous system tumor and liver cancer A composition comprising an active compound in an amount sufficient to achieve its intended purpose, such as prevention or treatment of any one disease.
このとき、治療有効量とは、疾患の症候を予防、緩和又は改善するか、又は治療される患者の生存を延長させるのに有効な量を意味する。 In this case, the therapeutically effective amount means an amount effective to prevent, alleviate or ameliorate the symptoms of the disease, or to prolong the survival of the treated patient.
本発明による医薬組成物は、組成物全重量に対して、前記式（１）の化合物又はその薬学的に許容される塩を０．１〜５０重量％で含むことができる。 The pharmaceutical composition according to the present invention may comprise the compound of formula (1) or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 50% by weight based on the total weight of the composition.
本発明による式（１）の化合物又はその薬学的許容される塩の使用量は、患者の年齢、性別、体重に応じて変わるが、０．０１〜１００ｍｇ／ｋｇ、好ましくは０．１〜１０ｍｇ／ｋｇの量を一日１回〜数回投与することができる。また、式（１）の化合物又はその薬学的許容される塩の投与量は、投与経路、疾患の程度、性別、体重、年齢などに応じて増減することができる。従って、前記投与量は、本発明の範囲を限定するものではない。 The amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof according to the present invention varies depending on the age, sex, and weight of the patient, but is 0.01 to 100 mg / kg, preferably 0.1 to 10 mg. / Kg dose can be administered once to several times a day. The dose of the compound of the formula (1) or a pharmaceutically acceptable salt thereof can be increased or decreased according to the administration route, the degree of the disease, sex, body weight, age and the like. Thus, the dosages do not limit the scope of the invention.
前記医薬組成物は、ラット、ハツカネズミ、家畜及びヒトなどの哺乳動物に多様な経路で投与することができる。 The pharmaceutical composition can be administered to mammals such as rats, mice, domestic animals and humans by various routes.
本発明による式（１）の化合物又はその薬学的に許容される塩は、５０％致死量（ＬＤ５０）は、少なくとも２ｇ／ｋｇ以上である。即ち、前記式（１）の化合物又はその薬学的に許容される塩は、十分に安定であり、本発明の医薬組成物に使用することができる。
また、本発明の式（１）の化合物又はこれの塩又はプロドラッグは、前記疾患及び疾患の治療のために他の化学療法剤と組み合わせてもよい。他の化学療法剤は、例えば、肺癌、乳癌、膀胱癌、骨癌、甲状腺癌、副甲状腺癌、直膓癌、前立腺癌、腎臓癌、咽喉癌、喉頭癌、食道癌、膵臓癌、大腸癌、胃癌、舌癌、皮膚癌、脳腫瘍、子宮癌、頭部又は頸部癌、胆のう癌、口腔癌、結腸癌、肛門癌、中枢神経系腫瘍、肝癌及び／又は結腸直腸癌の治療剤であってもよい。
The compound of formula (1) or a pharmaceutically acceptable salt thereof according to the present invention has a 50% lethal dose (LD 50 ) of at least 2 g / kg or more. That is, the compound of the formula (1) or a pharmaceutically acceptable salt thereof is sufficiently stable and can be used in the pharmaceutical composition of the present invention.
Further, the compound of the formula (1) or a salt or prodrug thereof of the present invention may be combined with other chemotherapeutic agents for treating the above-mentioned diseases and diseases. Other chemotherapeutic agents include, for example, lung, breast, bladder, bone, thyroid, parathyroid, colon, prostate, kidney, throat, larynx, esophagus, pancreatic, colon , Gastric cancer, tongue cancer, skin cancer, brain tumor, uterine cancer, head or neck cancer, gallbladder cancer, oral cancer, colon cancer, anal cancer, central nervous system tumor, liver cancer and / or colorectal cancer. You may.
＜実施例１＞５−（ヒドロキシメチル）−２，４−ジメチルピリジン−３−オール塩酸塩（２）の製造
ピリドキシン塩酸塩（１、１０．０ｇ、４８．６ｍｍｏｌ）の酢酸（４０ｍＬ）溶液に亜鉛（Ｚｎ）粉末（１２．７ｇ、０．１９５ｍｏｌ）を少量ずつ加えた後、混合物を２４時間還流撹拌した。反応液を室温に冷却した後、減圧ろ過し、アセトニトリル（ＣＨ３ＣＮ、５０ｍＬ）で洗浄した後、過量の塩酸−メタノール溶液（１５０ｍＬ）を濾液に加えた。氷冷下で、２時間撹拌した後、得られた懸濁液を減圧ろ過して、白色固体として目的化合物２（８．７ｇ、９４％）を得た。
1H-NMR ((CD3)2SO) δ 10.62 (br s, 1H), 8.08 (s, 1H), 5.70 (br s, 1H), 4.60 (s, 2H), 2.61 (s, 3H), 2.32 (s, 3H).
Example 1 Preparation of 5- (hydroxymethyl) -2,4-dimethylpyridin-3-ol hydrochloride (2) Pyridoxine hydrochloride (1, 10.0 g, 48.6 mmol) was added to a solution of acetic acid (40 mL). After zinc (Zn) powder (12.7 g, 0.195 mol) was added little by little, the mixture was stirred under reflux for 24 hours. The reaction solution was cooled to room temperature, vacuum filtered, washed with acetonitrile (CH 3 CN, 50mL), excessive amount of hydrochloric acid - was added methanol solution (150 mL) to the filtrate. After stirring for 2 hours under ice cooling, the resulting suspension was filtered under reduced pressure to obtain the target compound 2 (8.7 g, 94%) as a white solid.
1 H-NMR ((CD 3 ) 2 SO) δ 10.62 (br s, 1H), 8.08 (s, 1H), 5.70 (br s, 1H), 4.60 (s, 2H), 2.61 (s, 3H), 2.32 (s, 3H).
＜実施例２＞（５−（ベンジルオキシ）−４，６−ジメチルピリジン−３−イル）メタノール（３）の製造
化合物２（８．６ｇ、４５．７ｍｍｏｌ）のＤＭＦ（４５０ｍＬ）溶液に炭酸カリウム（１０７ｇ、０．７７６ｍｏｌ）と塩化ベンジル（２６．２ｍＬ、０．２２８ｍｏｌ）を加えた後、室温で２４時間撹拌した。反応液を減圧下濃縮した後、酢酸エチル（ＥｔＯＡｃ、１Ｌ）で希釈し、水（３×１００ｍＬ）で洗浄した。酢酸エチル溶液を飽和塩水で洗浄し、無水硫酸マグネシウム（ＭｇＳＯ４）で乾燥、ろ過し、減圧下濃縮した。残渣をカラムクロマトグラフィー（ＣＨ２Ｃｌ２：ＭｅＯＨ＝２０：１）で精製して、褐色固体として目的化合物３（８．２ｇ、７４％）を得た。
1H-NMR (CDCl3) δ 8.07 (s, 1H), 7.38-7.47 (m, 5H), 4.80 (s, 2H), 4.65 (s, 2H), 2.48 (s, 3H), 2.32 (s, 3H).
Example 2 Preparation of (5- (benzyloxy) -4,6-dimethylpyridin-3-yl) methanol (3) Potassium carbonate was added to a solution of compound 2 (8.6 g, 45.7 mmol) in DMF (450 mL). (107 g, 0.776 mol) and benzyl chloride (26.2 mL, 0.228 mol) were added, followed by stirring at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (EtOAc, 1 L), and washed with water (3 × 100 mL). The ethyl acetate solution was washed with saturated brine, dried over anhydrous magnesium sulfate (MgSO 4 ), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (CH 2 Cl 2 : MeOH = 20: 1) to obtain target compound 3 (8.2 g, 74%) as a brown solid.
1 H-NMR (CDCl 3 ) δ 8.07 (s, 1H), 7.38-7.47 (m, 5H), 4.80 (s, 2H), 4.65 (s, 2H), 2.48 (s, 3H), 2.32 (s, 3H).
＜実施例３＞３−ベンジルオキシ−５−クロロメチル−２，４−ジメチルピリジン塩酸塩（４）の製造
化合物３（２．８５ｇ、１１.７１ｍｍｏｌ）の１，２−ジクロロエタン（３５ｍＬ）溶液にＤＭＦ（０．０９ｍＬ、２３．４３ｍｍｏｌ）と塩化チオニル（１.７ｍＬ、２３．４３ｍｍｏｌ）を加え、８０℃で１時間撹拌した。反応液を室温に冷却した後、エチルエーテル（１５０ｍＬ）を反応液に加え、氷冷下で１時間撹拌した。析出された固体を減圧ろ過し、ろ過された固体をエチルエーテルで洗浄し、乾燥して、目的化合物４（３ｇ、８６％）を褐色の固体として得た。
1H-NMR (CDCl3) δ 8.19 (s, 1H), 7.34-7.44 (m, 5H), 4.81 (s, 2H), 4.56 (s, 2H), 2.50 (s, 3H), 2.32 (s, 3H).
Example 3 Preparation of 3-benzyloxy-5-chloromethyl-2,4-dimethylpyridine hydrochloride (4) A solution of compound 3 (2.85 g, 11.71 mmol) in 1,2-dichloroethane (35 mL) was prepared. DMF (0.09 mL, 23.43 mmol) and thionyl chloride (1.7 mL, 23.43 mmol) were added, and the mixture was stirred at 80 ° C. for 1 hour. After cooling the reaction solution to room temperature, ethyl ether (150 mL) was added to the reaction solution, and the mixture was stirred under ice cooling for 1 hour. The precipitated solid was filtered under reduced pressure, and the filtered solid was washed with ethyl ether and dried to obtain the target compound 4 (3 g, 86%) as a brown solid.
1 H-NMR (CDCl 3 ) δ 8.19 (s, 1H), 7.34-7.44 (m, 5H), 4.81 (s, 2H), 4.56 (s, 2H), 2.50 (s, 3H), 2.32 (s, 3H).
＜実施例４＞２−（５−ベンジルオキシ−４，６−ジメチルピリジン−３−イル）アセトニトリル（５）の製造
化合物４（９．９５ｇ、３８．０１ｍｍｏｌ）のＤＭＦ（５００ｍＬ）溶液にシアン化カリウム（ＫＣＮ、７．４２ｇ、１１４．０４ｍｍｏｌ）を加え、３０〜４０℃で２日間撹拌した。反応液を濃縮し、残渣を酢酸エチル（２Ｌ）で希釈し、水（４×２００ｍＬ）で洗浄した。酢酸エチル溶液を無水硫酸マグネシウムで乾燥、ろ過して、減圧下濃縮した。残渣をカラムクロマトグラフィー（ＣＨＣｌ３：ＭｅＯＨ＝５０：１→２０：１）で精製して、目的化合物５（８．０６ｇ、９５％）を褐色の固体として得た。
1H-NMR (CDCl3) δ 8.18 (s, 1H), 7.35-7.43 (m, 5H), 4.80 (s, 2H), 3.61 (s, 2H), 2.51 (s, 3H), 2.26 (s, 3H).
Example 4 Production of 2- (5-benzyloxy-4,6-dimethylpyridin-3-yl) acetonitrile (5) A solution of compound 4 (9.95 g, 38.01 mmol) in DMF (500 mL) was mixed with potassium cyanide (500 mL). KCN, 7.42 g, 114.04 mmol) was added, and the mixture was stirred at 30 to 40 ° C for 2 days. The reaction was concentrated and the residue was diluted with ethyl acetate (2L) and washed with water (4x200mL). The ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (CHCl 3 : MeOH = 50: 1 → 20: 1) to obtain the desired compound 5 (8.06 g, 95%) as a brown solid.
1 H-NMR (CDCl 3 ) δ 8.18 (s, 1H), 7.35-7.43 (m, 5H), 4.80 (s, 2H), 3.61 (s, 2H), 2.51 (s, 3H), 2.26 (s, 3H).
＜実施例５＞エチル２−（５−ヒドロキシ−４，６−ジメチルピリジン−３−イル）アセテート（６）の製造
化合物５（５００ｍｇ、１.９８ｍｍｏｌ）のエタノール（２０ｍＬ）溶液に濃硫酸（３．７ｍＬ、６９．３６ｍｍｏｌ）を加え、２４時間還流撹拌した。反応液を室温に冷却し、エタノール（１５０ｍＬ）を添加して、希釈した。少量の炭酸ナトリウム（Ｎａ２ＣＯ３、７．３５ｇ、６９．３６ｍｍｏｌ）を反応液に加え、室温で３時間撹拌した。反応液を濃縮し、残渣を酢酸エチル（１５０ｍＬ）で希釈した後、減圧ろ過して固体を濾別し、酢酸エチルで洗浄した。濾液を減圧下濃縮し、残渣をカラムクロマトグラフィー（ＣＨＣｌ３：ＭｅＯＨ＝７０：１→２０：１）で精製して、目的化合物６（３６６ｍｇ、８８％）を黄色の固体として得た。
1H-NMR (CDCl3) δ 7.80 (s, 1H), 6.96 (br s, 1H), 4.11 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.38 (s, 3H), 2.19 (s, 3H), 1.21 (t, J=7.1 Hz, 3H).
<Example 5> Preparation of ethyl 2- (5-hydroxy-4,6-dimethylpyridin-3-yl) acetate (6) A solution of compound 5 (500 mg, 1.98 mmol) in ethanol (20 mL) was concentrated sulfuric acid (3). (0.7 mL, 69.36 mmol) and stirred under reflux for 24 hours. The reaction was cooled to room temperature and diluted by adding ethanol (150 mL). A small amount of sodium carbonate (Na 2 CO 3 , 7.35 g, 69.36 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was diluted with ethyl acetate (150 mL), filtered under reduced pressure, and the solid was separated by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (CHCl 3 : MeOH = 70: 1 → 20: 1) to obtain the desired compound 6 (366 mg, 88%) as a yellow solid.
1 H-NMR (CDCl 3 ) δ 7.80 (s, 1H), 6.96 (br s, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 2.38 (s, 3H), 2.19 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).
＜実施例６＞エチル２−（５−ヒドロキシ−４，６−ジメチル−２−（フェニルジアゼニル）ピリジン−３−イル）アセテート（７）の製造
ビーカーに、化合物６（１ｇ、４．７８ｍｍｏｌ）を水−ＴＨＦ（テトラヒドロフラン）混合溶媒（１：１、３０ｍＬ）に溶解し、撹拌機とｐＨメーターを取り付けた後、氷冷下で冷却した。別途の三角フラスコにアニリン（０．４８ｍＬ、５．２６ｍｍｏｌ）を６Ｍ−塩酸（５ｍＬ）に溶解した後、氷冷下で冷却し、ＮａＮＯ２（亜窒酸ナトリウム、３６３ｍｇ、５．２６ｍｍｏｌ）の冷えた水（２ｍＬ）溶液を上記アニリン−塩酸溶液に少量ずつ加えて、ジアゾ化アニリン溶液を製造した。このジアゾ化アニリン溶液を化合物６の***液に少量ずつ添加した。同時に、１０Ｍ−水酸化ナトリウム溶液で反応液をｐＨ８に維持した。ジアゾ化アニリン溶液を全部添加した後、反応液を室温で２時間撹拌した。反応液を酢酸エチル（３×１５０ｍＬ）で抽出し、酢酸エチル溶液を飽和塩水で洗浄し、無水硫酸マグネシウムで乾燥、ろ過して、減圧下濃縮した。残渣をカラムクロマトグラフィー（ＣＨＣｌ３：ＭｅＯＨ＝８０：１→２０：１）で精製して、目的化合物７（１.３ｇ、８７％）を赤色の固体として得た。
1H-NMR (CDCl3) δ 7.32-7.37 (m, 4H), 7.08-7.13 (m, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.89 (s, 2H), 2.40 (s, 3H), 2.06 (s, 3H), 1.22 (t, J=7.1 Hz, 3H).
Example 6 Production of Ethyl 2- (5-hydroxy-4,6-dimethyl-2- (phenyldiazenyl) pyridin-3-yl) acetate (7) Compound 6 (1 g, 4.78 mmol) was placed in a beaker. After dissolving in a mixed solvent of water and THF (tetrahydrofuran) (1: 1, 30 mL), the mixture was cooled under ice-cooling after attaching a stirrer and a pH meter. In a separate Erlenmeyer flask, aniline (0.48 mL, 5.26 mmol) was dissolved in 6 M hydrochloric acid (5 mL), cooled under ice cooling, and cooled with NaNO 2 (sodium nitrite, 363 mg, 5.26 mmol). The water (2 mL) solution was added little by little to the aniline-hydrochloric acid solution to prepare a diazotized aniline solution. This diazotized aniline solution was added in small portions to the cold solution of compound 6. At the same time, the reaction solution was maintained at pH 8 with a 10 M sodium hydroxide solution. After all the diazotized aniline solution was added, the reaction was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate (3 × 150 mL), and the ethyl acetate solution was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (CHCl 3 : MeOH = 80: 1 → 20: 1) to obtain the desired compound 7 (1.3 g, 87%) as a red solid.
1 H-NMR (CDCl 3 ) δ 7.32-7.37 (m, 4H), 7.08-7.13 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.89 (s, 2H), 2.40 (s, 3H), 2.06 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H).
＜実施例７＞５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（８）の製造
化合物７（５５０ｍｇ、１.７５ｍｍｏｌ）の酢酸（３５ｍＬ）溶液に、亜鉛（Ｚｎ）粉末（３４４ｍｇ、５．２６ｍｍｏｌ）を少量ずつ添加し、１２時間還流撹拌した。反応液を室温で冷却した後、減圧ろ過して固体を濾別し、アセトニトリル（ＣＨ３ＣＮ）で洗浄した。濾液を濃縮した後、残渣をカラムクロマトグラフィー（ＣＨＣｌ３：ＭｅＯＨ＝８０：１→１０：１）で精製して目的化合物８（２７３ｍｇ、８７％）を褐色の固体として得た。
1H-NMR ((CD3)2SO) δ 10.4 (s, 1H), 8.05 (s, 1H), 3.38 (s, 2H), 2.27 (s, 3H), 2.07 (s, 3H).
<Example 7> Production of 5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (8) Compound 7 (550 mg, 1.75 mmol) in acetic acid ( (35 mL), zinc (Zn) powder (344 mg, 5.26 mmol) was added little by little to the solution, and the mixture was refluxed and stirred for 12 hours. The reaction solution was cooled at room temperature, filtered under reduced pressure, and the solid was separated by filtration and washed with acetonitrile (CH 3 CN). After concentrating the filtrate, the residue was purified by column chromatography (CHCl 3 : MeOH = 80: 1 → 10: 1) to obtain the desired compound 8 (273 mg, 87%) as a brown solid.
1 H-NMR ((CD 3 ) 2 SO) δ 10.4 (s, 1H), 8.05 (s, 1H), 3.38 (s, 2H), 2.27 (s, 3H), 2.07 (s, 3H).
＜実施例８−１＞（Ｚ）−３−ヘキシリデン−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−０１）の製造
化合物８（２０ｍｇ、０．１１２ｍｍｏｌ）のメタノール（１ｍＬ）溶液に、１−ヘキサナール（２０．７μＬ、０．１６８ｍｍｏｌ）とピペリジン（２２．３μＬ、０．２２４ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液中の固体を減圧ろ過した後、ろ過した固体を酢酸エチルで洗浄し、乾燥して、目的化合物Ｉ−０１（２６ｍｇ、８８％）を黄色の固体として得た。
1H-NMR ((CD3)2SO) δ 10.59 (s, 1H), 8.12 (s, 1H), 6.90 (t, J=7.7 Hz, 1H), 2.93 (q, J=7.5 Hz, 2H), 2.30 (s, 6H), 1.52-1.48 (m, 2H), 1.35-1.31 (m, 4H), 0.88 (t, J=6.9 Hz, 3H).
Example 8-1 Preparation of (Z) -3-hexylidene-5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I-01) To a solution of compound 8 (20 mg, 0.112 mmol) in methanol (1 mL) was added 1-hexanal (20.7 μL, 0.168 mmol) and piperidine (22.3 μL, 0.224 mmol), and the mixture was stirred at room temperature for 2 hours. After filtering the solid in the reaction solution under reduced pressure, the filtered solid was washed with ethyl acetate and dried to obtain the target compound I-01 (26 mg, 88%) as a yellow solid.
1 H-NMR ((CD 3 ) 2 SO) δ 10.59 (s, 1H), 8.12 (s, 1H), 6.90 (t, J = 7.7 Hz, 1H), 2.93 (q, J = 7.5 Hz, 2H) , 2.30 (s, 6H), 1.52-1.48 (m, 2H), 1.35-1.31 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H).
＜実施例８−２〜８−４６＞
前記実施例８−１で用いた１−ヘキサナール及びピペリジンの代わりに目的化合物に相応する化合物をそれぞれ使用したこと以外は、実施例８−１と同様にして、下記実施例８−２〜８−４６の目的化合物を製造した。
<Examples 8-2 to 8-46>
The same procedures as in Example 8-1 were repeated except that compounds corresponding to the target compound were used instead of 1-hexanal and piperidine used in Example 8-1. 46 target compounds were prepared.
＜実施例８−２＞（Ｚ）−３−（２−エチルブチリデン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−０２）の製造
1H-NMR ((CD3)2SO) δ 11.07 (s, 1H), 6.71 (d, J = 10.4 Hz, 1H), 3.82 (s, 1H), 2.35 (d, J = 1.6 Hz, 6H), 1.62-1.49 (m, 2H), 1.42-1.29 (m, 2H), 0.83 (t, J = 7.3 Hz, 6H).
<Example 8-2> (Z) -3- (2-ethylbutylidene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-02)
1 H-NMR ((CD 3 ) 2 SO) δ 11.07 (s, 1H), 6.71 (d, J = 10.4 Hz, 1H), 3.82 (s, 1H), 2.35 (d, J = 1.6 Hz, 6H) , 1.62-1.49 (m, 2H), 1.42-1.29 (m, 2H), 0.83 (t, J = 7.3 Hz, 6H).
＜実施例８−３＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（３−メチルブタ−２−エンイリデン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−０３）の製造
1H-NMR (CD3OD) δ 7.86 (d, J = 12.1 Hz, 1H), 7.70 (d, J = 11.9 Hz, 1H), 2.63 (s, 3H), 2.53 (s, 3H), 2.07 (s, 6H).
<Example 8-3> (Z) -5-Hydroxy-4,6-dimethyl-3- (3-methylbut-2-enylidene) -1H-pyrrolo [2,3-b] pyridine-2 (3H)- Production of ON (I-03)
1 H-NMR (CD 3 OD) δ 7.86 (d, J = 12.1 Hz, 1H), 7.70 (d, J = 11.9 Hz, 1H), 2.63 (s, 3H), 2.53 (s, 3H), 2.07 ( s, 6H).
＜実施例８−４＞（Ｚ）−５−ヒドロキシ−３−（（Ｅ）−３−（４−ヒドロキシ−３−メトキシフェニル）アリリデン）−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−０４）の製造
1H-NMR ((CD3)2SO) δ 11.05 (s, 1H), 8.36 (dd, J = 15.5, 11.4 Hz, 1H), 7.53 (d, J = 11.5 Hz, 1H), 7.23 (d, J = 15.5 Hz, 1H), 7.07 (d, J = 9.4 Hz, 2H), 6.85 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H).
Example 8-4 (Z) -5-hydroxy-3-((E) -3- (4-hydroxy-3-methoxyphenyl) allylidene) -4,6-dimethyl-1H-pyrrolo [2,3 -B] Preparation of pyridin-2 (3H) -one (I-04)
1 H-NMR ((CD 3 ) 2 SO) δ 11.05 (s, 1H), 8.36 (dd, J = 15.5, 11.4 Hz, 1H), 7.53 (d, J = 11.5 Hz, 1H), 7.23 (d, J = 15.5 Hz, 1H), 7.07 (d, J = 9.4 Hz, 2H), 6.85 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H).
＜実施例８−５＞（Ｚ）−３−（シクロヘキシルメチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−０５）の製造
1H-NMR (CD3OD) δ 6.80 (d, J = 9.8 Hz, 1H), 3.83 (d, J = 10.1 Hz, 1H), 2.38 (d, J = 1.8 Hz, 6H), 1.80 (d, J = 11.4 Hz, 4H), 1.34 (dt, J = 20.7, 11.4 Hz, 6H).
Example 8-5 (Z) -3- (cyclohexylmethylene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I-05 )Manufacturing of
1 H-NMR (CD 3 OD) δ 6.80 (d, J = 9.8 Hz, 1H), 3.83 (d, J = 10.1 Hz, 1H), 2.38 (d, J = 1.8 Hz, 6H), 1.80 (d, J = 11.4 Hz, 4H), 1.34 (dt, J = 20.7, 11.4 Hz, 6H).
＜実施例８−６＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（４−メチルベンジリデン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−０６）の製造
1H-NMR (CD3OD) δ 8.09 (d, J = 8.1 Hz, 2H), 7.97 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 2.71 (s, 3H), 2.56 (s, 3H), 2.40 (s, 3H).
Example 8-6 (Z) -5-Hydroxy-4,6-dimethyl-3- (4-methylbenzylidene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I -06) Production
1 H-NMR (CD 3 OD) δ 8.09 (d, J = 8.1 Hz, 2H), 7.97 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 2.71 (s, 3H), 2.56 ( s, 3H), 2.40 (s, 3H).
＜実施例８−７＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（２−ニトロベンジリデン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−０７）の製造
1H-NMR (CD3OD) δ 8.40 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.78-7.62 (m, 4H), 2.69 (s, 3H), 2.57 (s, 3H).
<Example 8-7> (Z) -5-hydroxy-4,6-dimethyl-3- (2-nitrobenzylidene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I -07) Production
1 H-NMR (CD 3 OD) δ 8.40 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.78-7.62 (m, 4H), 2.69 (s, 3H), 2.57 (s, 3H).
＜実施例８−８＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（４−ニトロベンジリデン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−０８）の製造
1H-NMR (CD3OD) δ 8.28 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 2.74 (s, 3H), 2.60 (s, 3H).
<Example 8-8> (Z) -5-Hydroxy-4,6-dimethyl-3- (4-nitrobenzylidene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I -08) Production
1 H-NMR (CD 3 OD) δ 8.28 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 2.74 (s, 3H ), 2.60 (s, 3H).
＜実施例８−９＞（Ｚ）−３−（４−フルオロベンジリデン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−０９）の製造
1H-NMR (CD3OD) δ 8.31-8.20 (m, 2H), 8.03 (s, 1H), 7.24-7.14 (m, 2H), 2.73 (s, 3H), 2.57 (s, 3H).
<Example 8-9> (Z) -3- (4-Fluorobenzylidene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I -09) Production
1 H-NMR (CD 3 OD) δ 8.31-8.20 (m, 2H), 8.03 (s, 1H), 7.24-7.14 (m, 2H), 2.73 (s, 3H), 2.57 (s, 3H).
＜実施例８−１０＞（Ｚ）−３−（４−クロロベンジリデン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−１０）の製造
1H-NMR ((CD3)2SO) δ 11.27 (s, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.74 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 2.52 (s, 3H), 2.40 (s, 3H).
<Example 8-10> (Z) -3- (4-chlorobenzylidene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I Production of -10)
1 H-NMR ((CD 3 ) 2 SO) δ 11.27 (s, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.74 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H) , 2.52 (s, 3H), 2.40 (s, 3H).
＜実施例８−１１＞（Ｚ）−５−ヒドロキシ−３−（２−ヒドロキシベンジリデン）−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−１１）の製造
1H-NMR ((CD3)2SO) δ 11.06 (s, 1H), 10.55-10.04 (m, 1H), 8.31 (d, J = 7.7 Hz, 1H), 7.98 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 2.45 (s, 3H), 2.37 (s, 3H).
Example 8-11 (Z) -5-hydroxy-3- (2-hydroxybenzylidene) -4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I Production of -11)
1 H-NMR ((CD 3 ) 2 SO) δ 11.06 (s, 1H), 10.55-10.04 (m, 1H), 8.31 (d, J = 7.7 Hz, 1H), 7.98 (s, 1H), 7.25 ( t, J = 7.6 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.80 (t, J = 7.5 Hz, 1H), 2.45 (s, 3H), 2.37 (s, 3H).
＜実施例８−１２＞（Ｚ）−５−ヒドロキシ−３−（２−メトキシベンジリデン）−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−１２）の製造
1H-NMR ((CD3)2SO) δ 10.80 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 3.86 (s, 3H), 2.42 (s, 3H), 2.35 (s, 3H).
Example 8-12 (Z) -5-Hydroxy-3- (2-methoxybenzylidene) -4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I -12) Manufacturing
1 H-NMR ((CD 3 ) 2 SO) δ 10.80 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.40 (t, J = 7.8 Hz, 1H) , 7.06 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 3.86 (s, 3H), 2.42 (s, 3H), 2.35 (s, 3H).
＜実施例８−１３＞（Ｚ）−５−ヒドロキシ−３−（３−メトキシベンジリデン）−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−１３）の製造
1H-NMR ((CD3)2SO) δ 11.21 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.01 (dd, J = 8.2, 2.5 Hz, 1H), 3.80 (s, 3H), 2.53 (s, 3H), 2.40 (s, 3H).
Example 8-13 (Z) -5-Hydroxy-3- (3-methoxybenzylidene) -4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I -13) Manufacturing
1 H-NMR ((CD 3 ) 2 SO) δ 11.21 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.01 (dd, J = 8.2, 2.5 Hz, 1H), 3.80 (s, 3H), 2.53 (s, 3H), 2.40 (s, 3H).
＜実施例８−１４＞（Ｚ）−５−ヒドロキシ−３−（４−メトキシベンジリデン）−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−１４）の製造
1H-NMR (CD3OD) δ 8.32 (d, J = 8.9 Hz, 2H), 7.99 (s, 1H), 7.02 (t, J = 6.1 Hz, 2H), 3.89 (d, J = 3.0 Hz, 3H), 2.73 (s, 3H), 2.56 (s, 3H).
<Example 8-14> (Z) -5-Hydroxy-3- (4-methoxybenzylidene) -4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I -14) Manufacturing
1 H-NMR (CD 3 OD) δ 8.32 (d, J = 8.9 Hz, 2H), 7.99 (s, 1H), 7.02 (t, J = 6.1 Hz, 2H), 3.89 (d, J = 3.0 Hz, 3H), 2.73 (s, 3H), 2.56 (s, 3H).
＜実施例８−１５＞（Ｚ）−３−（２，５−ジメトキシベンジリデン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−１５）の製造
1H-NMR (CD3OD) δ 8.35 (s, 1H), 8.16 (d, J = 2.9 Hz, 1H), 7.13-6.94 (m, 2H), 3.91-3.87 (m, 3H), 3.82-3.77 (m, 3H), 2.69-2.60 (m, 3H), 2.56-2.51 (m, 3H).
Example 8-15 (Z) -3- (2,5-dimethoxybenzylidene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one Production of (I-15)
1 H-NMR (CD 3 OD) δ 8.35 (s, 1H), 8.16 (d, J = 2.9 Hz, 1H), 7.13-6.94 (m, 2H), 3.91-3.87 (m, 3H), 3.82-3.77 (m, 3H), 2.69-2.60 (m, 3H), 2.56-2.51 (m, 3H).
＜実施例８−１６＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（３，４，５−トリメトキシベンジリデン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−１６）の製造
1H-NMR ((CD3)2SO) δ 11.20 (s, 1H), 7.76 (s, 2H), 7.72 (s, 1H), 3.82 (s, 6H), 3.74 (s, 3H), 2.54 (s, 3H), 2.39 (s, 3H).
<Example 8-16> (Z) -5-hydroxy-4,6-dimethyl-3- (3,4,5-trimethoxybenzylidene) -1H-pyrrolo [2,3-b] pyridine-2 (3H Preparation of) -one (I-16)
1 H-NMR ((CD 3 ) 2 SO) δ 11.20 (s, 1H), 7.76 (s, 2H), 7.72 (s, 1H), 3.82 (s, 6H), 3.74 (s, 3H), 2.54 ( s, 3H), 2.39 (s, 3H).
＜実施例８−１７＞（Ｚ）−３−（５−ブロモ−２−メトキシベンジリデン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−１７）の製造
1H-NMR (CD3OD) δ 8.45 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.58 (dd, J = 8.9, 2.5 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 3.93 (s, 3H), 2.68 (s, 3H), 2.57 (s, 3H).
Example 8-17 (Z) -3- (5-bromo-2-methoxybenzylidene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridine-2 (3H) Production of -ON (I-17)
1 H-NMR (CD 3 OD) δ 8.45 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.58 (dd, J = 8.9, 2.5 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 3.93 (s, 3H), 2.68 (s, 3H), 2.57 (s, 3H).
＜実施例８−１８＞（Ｚ）−３−（４−（ジメチルアミノ）ベンジリデン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−１８）の製造
1H-NMR ((CD3)2SO) δ 10.45 (s, 1H), 8.28 (d, J = 9.0 Hz, 2H), 7.94 (br s, 1H), 7.56 (s, 1H), 6.74 (d, J = 9.0 Hz, 2H), 3.03 (s, 6H), 2.47 (s, 3H), 2.33 (s, 3H).
Example 8-18 (Z) -3- (4- (dimethylamino) benzylidene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridine-2 (3H)- Production of ON (I-18)
1 H-NMR ((CD 3 ) 2 SO) δ 10.45 (s, 1H), 8.28 (d, J = 9.0 Hz, 2H), 7.94 (br s, 1H), 7.56 (s, 1H), 6.74 (d , J = 9.0 Hz, 2H), 3.03 (s, 6H), 2.47 (s, 3H), 2.33 (s, 3H).
＜実施例８−１９＞（Ｚ）−３−（２，２−ジフェニルエチリデン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−１９）の製造
1H-NMR (CD3OD) δ 7.72 (d, J = 10.8 Hz, 1H), 7.35-7.24 (m, 11H), 6.78 (d, J = 10.7 Hz, 1H), 2.61 (s, 3H), 2.55 (s, 3H).
Example 8-19 (Z) -3- (2,2-diphenylethylidene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one Production of (I-19)
1 H-NMR (CD 3 OD) δ 7.72 (d, J = 10.8 Hz, 1H), 7.35-7.24 (m, 11H), 6.78 (d, J = 10.7 Hz, 1H), 2.61 (s, 3H), 2.55 (s, 3H).
＜実施例８−２０＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（ナフタレン−２−イルメチレン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−２０）の製造
1H-NMR ((CD3)2SO) δ 11.33 (s, 1H), 8.59 (s, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.99-7.83 (m, 4H), 7.56 (s, 2H), 2.56 (s, 3H), 2.40 (s, 3H).
<Example 8-20> (Z) -5-Hydroxy-4,6-dimethyl-3- (naphthalen-2-ylmethylene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-20)
1 H-NMR ((CD 3 ) 2 SO) δ 11.33 (s, 1H), 8.59 (s, 1H), 8.28 (d, J = 8.5 Hz, 1H), 7.99-7.83 (m, 4H), 7.56 ( s, 2H), 2.56 (s, 3H), 2.40 (s, 3H).
＜実施例８−２１＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（ピリジン−２−イルメチレン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−２１）の製造
1H-NMR (CD3OD) δ 9.07 (dd, J = 5.8, 1.3 Hz, 1H), 8.75 (td, J = 7.9, 1.6 Hz, 1H), 8.56 (d, J = 8.1 Hz, 1H), 8.22-8.14 (m, 1H), 8.05 (s, 1H), 2.77 (s, 3H), 2.58 (s, 3H).
<Example 8-21> (Z) -5-Hydroxy-4,6-dimethyl-3- (pyridin-2-ylmethylene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-21)
1 H-NMR (CD 3 OD) δ 9.07 (dd, J = 5.8, 1.3 Hz, 1H), 8.75 (td, J = 7.9, 1.6 Hz, 1H), 8.56 (d, J = 8.1 Hz, 1H), 8.22-8.14 (m, 1H), 8.05 (s, 1H), 2.77 (s, 3H), 2.58 (s, 3H).
＜実施例８−２２＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（ピリジン−３−イルメチレン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−２２）の製造
1H-NMR (CD3OD) δ 9.45 (s, 1H), 9.02 (d, J = 8.2 Hz, 1H), 8.86 (d, J = 5.8 Hz, 1H), 8.16 (dd, J = 8.0, 5.9 Hz, 1H), 8.07 (s, 1H), 2.73 (s, 3H), 2.57 (s, 3H).
<Example 8-22> (Z) -5-Hydroxy-4,6-dimethyl-3- (pyridin-3-ylmethylene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-22)
1 H-NMR (CD 3 OD) δ 9.45 (s, 1H), 9.02 (d, J = 8.2 Hz, 1H), 8.86 (d, J = 5.8 Hz, 1H), 8.16 (dd, J = 8.0, 5.9 Hz, 1H), 8.07 (s, 1H), 2.73 (s, 3H), 2.57 (s, 3H).
＜実施例８−２３＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（ピリジン−４−イルメチレン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−２３）の製造
1H-NMR (CD3OD) δ 8.83 (d, J = 6.8 Hz, 2H), 8.41 (d, J = 6.3 Hz, 2H), 7.87 (s, 1H), 2.59 (s, 3H), 2.46 (s, 3H).
<Example 8-23> (Z) -5-Hydroxy-4,6-dimethyl-3- (pyridin-4-ylmethylene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-23)
1 H-NMR (CD 3 OD) δ 8.83 (d, J = 6.8 Hz, 2H), 8.41 (d, J = 6.3 Hz, 2H), 7.87 (s, 1H), 2.59 (s, 3H), 2.46 ( s, 3H).
＜実施例８−２４＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（キノリン−２−イルメチレン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−２４）の製造
1H-NMR (CD3OD) δ 9.27 (d, J = 8.6 Hz, 1H), 8.53 (d, J = 8.6 Hz, 1H), 8.43-8.20 (m, 5H), 8.06 (dd, J = 11.1, 4.1 Hz, 1H), 2.83 (s, 3H), 2.61 (s, 3H).
<Example 8-24> (Z) -5-Hydroxy-4,6-dimethyl-3- (quinolin-2-ylmethylene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-24)
1 H-NMR (CD 3 OD) δ 9.27 (d, J = 8.6 Hz, 1H), 8.53 (d, J = 8.6 Hz, 1H), 8.43-8.20 (m, 5H), 8.06 (dd, J = 11.1 , 4.1 Hz, 1H), 2.83 (s, 3H), 2.61 (s, 3H).
＜実施例８−２５＞（Ｚ）−３−（（１Ｈ−インドール−４−イル）メチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−２５）の製造
1H-NMR ((CD3)2SO) δ 11.38 (s, 1H), 10.99 (s, 1H), 8.39 (d, J = 7.5 Hz, 1H), 8.12 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.15 (t, J = 7.8 Hz, 1H), 6.67 (s, 1H), 2.59 (s, 3H), 2.39 (s, 3H).
Example 8-25 (Z) -3-((1H-indol-4-yl) methylene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridine-2 ( Preparation of 3H) -one (I-25)
1 H-NMR ((CD 3 ) 2 SO) δ 11.38 (s, 1H), 10.99 (s, 1H), 8.39 (d, J = 7.5 Hz, 1H), 8.12 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.15 (t, J = 7.8 Hz, 1H), 6.67 (s, 1H), 2.59 (s, 3H), 2.39 (s, 3H).
＜実施例８−２６＞（Ｚ）−３−（（１Ｈ−インドール−３−イル）メチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−２６）の製造
1H-NMR ((CD3)2SO) δ 12.40 (d, J = 2.4 Hz, 1H), 11.64 (s, 1H), 9.37 (d, J = 3.0 Hz, 1H), 8.15 (s, 1H), 7.91 (dd, J = 6.4, 2.6 Hz, 1H), 7.54 (dd, J = 6.2, 2.8 Hz, 1H), 7.29-7.23 (m, 2H), 2.69 (s, 3H), 2.44 (s, 3H).
<Example 8-26> (Z) -3-((1H-indol-3-yl) methylene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridine-2 ( Preparation of 3H) -one (I-26)
1 H-NMR ((CD 3 ) 2 SO) δ 12.40 (d, J = 2.4 Hz, 1H), 11.64 (s, 1H), 9.37 (d, J = 3.0 Hz, 1H), 8.15 (s, 1H) , 7.91 (dd, J = 6.4, 2.6 Hz, 1H), 7.54 (dd, J = 6.2, 2.8 Hz, 1H), 7.29-7.23 (m, 2H), 2.69 (s, 3H), 2.44 (s, 3H ).
＜実施例８−２７＞（Ｚ）−３−（フラン−２−イルメチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−２７）の製造
1H-NMR ((CD3)2SO) δ 10.74 (s, 1H), 8.23 (d, J = 3.5 Hz, 1H), 8.17 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.45 (s, 1H), 6.73 (dd, J = 3.5, 1.7 Hz, 1H), 2.43 (s, 3H), 2.33 (s, 3H).
<Example 8-27> (Z) -3- (furan-2-ylmethylene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-27)
1 H-NMR ((CD 3 ) 2 SO) δ 10.74 (s, 1H), 8.23 (d, J = 3.5 Hz, 1H), 8.17 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H) , 7.45 (s, 1H), 6.73 (dd, J = 3.5, 1.7 Hz, 1H), 2.43 (s, 3H), 2.33 (s, 3H).
＜実施例８−２８＞（Ｚ）−３−（フラン−３−イルメチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−２８）の製造
1H-NMR (CD3OD) δ 10.77 (s, 1H), 8.78-8.64 (m, 1H), 8.20 (s, 1H), 7.76 (t, J = 1.5 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J = 1.6 Hz, 1H), 2.43 (s, 3H), 2.31 (s, 3H).
Example 8-28 (Z) -3- (furan-3-ylmethylene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-28)
1 H-NMR (CD 3 OD) δ 10.77 (s, 1H), 8.78-8.64 (m, 1H), 8.20 (s, 1H), 7.76 (t, J = 1.5 Hz, 1H), 7.52 (s, 1H) ), 7.40 (d, J = 1.6 Hz, 1H), 2.43 (s, 3H), 2.31 (s, 3H).
＜実施例８−２９＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（チオフェン−２−イルメチレン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−２９）の製造
1H-NMR ((CD3)2SO) δ 10.82 (s, 1H), 8.25 (br s, 1H), 7.96 (s, 1H), 7.92 (d, J = 3.0 Hz, 1H), 7.87 (d, J = 5.1 Hz, 1H), 7.21 (dd, J = 5.1, 3.7 Hz, 1H), 2.48 (s, 3H), 2.33 (s, 3H).
<Example 8-29> (Z) -5-Hydroxy-4,6-dimethyl-3- (thiophen-2-ylmethylene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-29)
1 H-NMR ((CD 3 ) 2 SO) δ 10.82 (s, 1H), 8.25 (br s, 1H), 7.96 (s, 1H), 7.92 (d, J = 3.0 Hz, 1H), 7.87 (d , J = 5.1 Hz, 1H), 7.21 (dd, J = 5.1, 3.7 Hz, 1H), 2.48 (s, 3H), 2.33 (s, 3H).
＜実施例８−３０＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（（３−メチルチオフェン−２−イル）メチレン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−３０）の製造
1H-NMR (CD3OD) δ 8.18 (s, 1H), 7.82 (d, J = 5.1 Hz, 1H), 7.11 (d, J=5.1 Hz, 1H), 2.73 (s, 3H), 2.54 (s, 6H).
Example 8-30 (Z) -5-hydroxy-4,6-dimethyl-3-((3-methylthiophen-2-yl) methylene) -1H-pyrrolo [2,3-b] pyridine-2 Production of (3H) -one (I-30)
1 H-NMR (CD 3 OD) δ 8.18 (s, 1H), 7.82 (d, J = 5.1 Hz, 1H), 7.11 (d, J = 5.1 Hz, 1H), 2.73 (s, 3H), 2.54 ( s, 6H).
＜実施例８−３１＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（チオフェン−２−イルメチレン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−３１）の製造
1H-NMR (CD3OD) δ 8.15 (s, 1H), 7.78 (d, J = 3.8 Hz, 1H), 6.97 (dd, J = 3.8, 0.9 Hz, 1H), 2.71 (s, 3H), 2.58 (s, 3H), 2.54 (s, 3H).
<Example 8-31> (Z) -5-hydroxy-4,6-dimethyl-3- (thiophen-2-ylmethylene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-31)
1 H-NMR (CD 3 OD) δ 8.15 (s, 1H), 7.78 (d, J = 3.8 Hz, 1H), 6.97 (dd, J = 3.8, 0.9 Hz, 1H), 2.71 (s, 3H), 2.58 (s, 3H), 2.54 (s, 3H).
＜実施例８−３２＞（Ｚ）−３−（（１Ｈ−ピロール−３−イル）メチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−３２）の製造
1H-NMR ((CD3)2SO) δ 13.18 (s, 1H), 11.53 (s, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 7.03 (s, 1H), 6.40- 6.34 (m, 1H), 2.53 (s, 3H), 2.40 (s, 3H).
<Example 8-32> (Z) -3-((1H-pyrrol-3-yl) methylene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridine-2 ( Preparation of 3H) -one (I-32)
1 H-NMR ((CD 3 ) 2 SO) δ 13.18 (s, 1H), 11.53 (s, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 7.03 (s, 1H), 6.40- 6.34 (m, 1H), 2.53 (s, 3H), 2.40 (s, 3H).
＜実施例８−３３＞（Ｚ）−３−（（１Ｈ−イミダゾール−２−イル）メチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−３３）の製造
1H-NMR ((CD3)2SO) δ 14.91 (br s, 1H), 11.66 (s, 1H), 8.62 (s, 1H), 7.85 (d, J = 1.1 Hz, 2H), 7.76 (s, 1H), 2.46 (s, 3H), 2.37 (s, 3H).
<Example 8-33> (Z) -3-((1H-Imidazol-2-yl) methylene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridine-2 ( Preparation of 3H) -one (I-33)
1 H-NMR ((CD 3 ) 2 SO) δ 14.91 (br s, 1H), 11.66 (s, 1H), 8.62 (s, 1H), 7.85 (d, J = 1.1 Hz, 2H), 7.76 (s , 1H), 2.46 (s, 3H), 2.37 (s, 3H).
＜実施例８−３４＞（Ｚ）−３−（（１Ｈ−イミダゾール−４−イル）メチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−３４）の製造
1H-NMR ((CD3)2SO) δ 13.67 (s, 1H), 11.06 (s, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 2.45 (s, 3H), 2.33 (s, 3H).
Example 8-34 (Z) -3-((1H-imidazol-4-yl) methylene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3-b] pyridine-2 ( Preparation of 3H) -one (I-34)
1 H-NMR ((CD 3 ) 2 SO) δ 13.67 (s, 1H), 11.06 (s, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 2.45 ( s, 3H), 2.33 (s, 3H).
＜実施例８−３５＞（Ｚ）−５−ヒドロキシ−４，６−ジメチル−３−（チアゾール−２−イルメチレン）−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−３５）の製造
1H-NMR ((CD3)2SO) δ 10.99 (s, 1H), 8.31 (s, 1H), 8.09 (d, J = 3.1 Hz, 1H), 8.00 (d, J = 3.1 Hz, 1H), 7.96 (s, 1H), 2.48 (s, 3H), 2.35 (s, 3H).
<Example 8-35> (Z) -5-hydroxy-4,6-dimethyl-3- (thiazol-2-ylmethylene) -1H-pyrrolo [2,3-b] pyridin-2 (3H) -one ( Production of I-35)
1 H-NMR ((CD 3 ) 2 SO) δ 10.99 (s, 1H), 8.31 (s, 1H), 8.09 (d, J = 3.1 Hz, 1H), 8.00 (d, J = 3.1 Hz, 1H) , 7.96 (s, 1H), 2.48 (s, 3H), 2.35 (s, 3H).
＜実施例８−３６＞（Ｚ）−３−（（３，５−ジメチル−１Ｈ−ピロール−２−イル）メチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−３６）の製造
1H-NMR ((CD3)2SO) δ 13.26 (s, 1H), 10.99 (s, 1H), 8.13 (s, 1H), 7.43 (s, 1H), 6.00 (d, J = 2.2 Hz, 1H), 2.46 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H).
Example 8-36 (Z) -3-((3,5-dimethyl-1H-pyrrol-2-yl) methylene) -5-hydroxy-4,6-dimethyl-1H-pyrrolo [2,3- b] Production of pyridin-2 (3H) -one (I-36)
1 H-NMR ((CD 3 ) 2 SO) δ 13.26 (s, 1H), 10.99 (s, 1H), 8.13 (s, 1H), 7.43 (s, 1H), 6.00 (d, J = 2.2 Hz, 1H), 2.46 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H).
＜実施例８−３７＞（Ｚ）−５−（（５−ヒドロキシ−４，６−ジメチル−２−オキソ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３（２Ｈ）−イリデン）メチル）−２，４−ジメチル−１Ｈ−ピロール−３−カルボン酸（Ｉ−３７）の製造
1H-NMR ((CD3)2SO) δ 13.72 (s, 1H), 12.08 (br s, 1H), 11.11 (s, 1H), 8.17 (br s, 1H), 7.49 (s, 1H), 2.52 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H).
<Example 8-37> (Z) -5-((5-hydroxy-4,6-dimethyl-2-oxo-1H-pyrrolo [2,3-b] pyridine-3 (2H) -ylidene) methyl) Production of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid (I-37)
1 H-NMR ((CD 3 ) 2 SO) δ 13.72 (s, 1H), 12.08 (br s, 1H), 11.11 (s, 1H), 8.17 (br s, 1H), 7.49 (s, 1H), 2.52 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H).
＜実施例８−３８＞（（Ｚ）−エチル−５−（（５−ヒドロキシ−４，６−ジメチル−２−オキソ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３（２Ｈ）−イリデン）メチル）−２，４−ジメチル−１Ｈ−ピロール−３−カルボキシレート（Ｉ−３８）の製造
1H-NMR ((CD3)2SO) δ 13.8 (s, 1H), 11.19 (br s, 1H), 8.25 (br s, 1H), 7.48 (s, 1H), 4.25-4.13 (m, 2H), 2.50-2.46 (m, 6H), 2.42 (s, 3H), 2.33 (s, 3H), 1.33-1.25 (m, 3H).
Example 8-38 ((Z) -Ethyl-5-((5-hydroxy-4,6-dimethyl-2-oxo-1H-pyrrolo [2,3-b] pyridine-3 (2H) -ylidene) ) Preparation of methyl) -2,4-dimethyl-1H-pyrrole-3-carboxylate (I-38)
1 H-NMR ((CD 3 ) 2 SO) δ 13.8 (s, 1H), 11.19 (br s, 1H), 8.25 (br s, 1H), 7.48 (s, 1H), 4.25-4.13 (m, 2H ), 2.50-2.46 (m, 6H), 2.42 (s, 3H), 2.33 (s, 3H), 1.33-1.25 (m, 3H).
＜実施例８−３９＞（Ｚ）−Ｎ−（２−（ジエチルアミノ）エチル）−５−（（５−ヒドロキシ−４，６−ジメチル−２−オキソ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３（２Ｈ）−イリデン）メチル）−２，４−ジメチル−１Ｈ−ピロール−３−カルボキサミド（Ｉ−３９）の製造
1H-NMR ((CD3)2SO) δ 13.50 (s, 1H), 11.03 (s, 1H), 8.13 (br s, 1H), 7.42 (s, 1H), 7.36 (t, J = 5.2 Hz, 1H), 3.30-3.21 (m, 2H), 2.50-2.37 (m, 12H), 2.30 (s, 6H), 0.95 (t, J = 7.0 Hz, 6H).
<Example 8-39> (Z) -N- (2- (diethylamino) ethyl) -5-((5-hydroxy-4,6-dimethyl-2-oxo-1H-pyrrolo [2,3-b] Production of pyridine-3 (2H) -ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxamide (I-39)
1 H-NMR ((CD 3 ) 2 SO) δ 13.50 (s, 1H), 11.03 (s, 1H), 8.13 (br s, 1H), 7.42 (s, 1H), 7.36 (t, J = 5.2 Hz , 1H), 3.30-3.21 (m, 2H), 2.50-2.37 (m, 12H), 2.30 (s, 6H), 0.95 (t, J = 7.0 Hz, 6H).
＜実施例８−４０＞（Ｚ）−Ｎ−（２−（エチルアミノ）エチル）−５−（（５−ヒドロキシ−４，６−ジメチル−２−オキソ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３（２Ｈ）−イリデン）メチル）−２，４−ジメチル−１Ｈ−ピロール−３−カルボキサミド（Ｉ−４０）の製造
1H-NMR (CD3OD) δ 13.30 (s, 1H), 7.76 (s, 1H), 3.69 (s, 2H), 3.25 (s, 2H), 3.13 (s, 2H), 2.71 (s, 3H), 2.56-2.38 (m, 9H), 1.35 (s, 3H).
<Example 8-40> (Z) -N- (2- (ethylamino) ethyl) -5-((5-hydroxy-4,6-dimethyl-2-oxo-1H-pyrrolo [2,3-b Production of pyridine-3 (2H) -ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxamide (I-40)
1 H-NMR (CD 3 OD) δ 13.30 (s, 1H), 7.76 (s, 1H), 3.69 (s, 2H), 3.25 (s, 2H), 3.13 (s, 2H), 2.71 (s, 3H) ), 2.56-2.38 (m, 9H), 1.35 (s, 3H).
＜実施例８−４１＞（Ｚ）−Ｎ−シクロヘキシル−５−（（５−ヒドロキシ−４，６−ジメチル−２−オキソ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３（２Ｈ）−イリデン）メチル）−２，４−ジメチル−１Ｈ−ピロール−３−カルボキサミド（Ｉ−４１）の製造
1H-NMR ((CD3)2SO) δ 13.49 (s, 1H), 11.08 (br s, 1H), 8.21 (br s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 3.78-3.62 (m, 1H), 2.46 (s, 3H), 2.40 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.85-1.66 (m, 4H), 1.63-1.53 (m, 1H), 1.36-1.07 (m, 5H).
Example 8-41 (Z) -N-cyclohexyl-5-((5-hydroxy-4,6-dimethyl-2-oxo-1H-pyrrolo [2,3-b] pyridine-3 (2H)- Production of (ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxamide (I-41)
1 H-NMR ((CD 3 ) 2 SO) δ 13.49 (s, 1H), 11.08 (br s, 1H), 8.21 (br s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.45 ( s, 1H), 3.78-3.62 (m, 1H), 2.46 (s, 3H), 2.40 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.85-1.66 (m, 4H) , 1.63-1.53 (m, 1H), 1.36-1.07 (m, 5H).
＜実施例８−４２＞（Ｚ）−５−（（５−ヒドロキシ−４，６−ジメチル−２−オキソ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−３（２Ｈ）−イリデン）メチル）−２，４−ジメチル−Ｎ−（２−（ピペリジン−１−イル）エチル）−１Ｈ−ピロール−３−カルボキサミド（Ｉ−４２）の製造
1H-NMR ((CD3)2SO) δ 13.54 (s, 1H), 7.48-7.42 (m, 2H), 3.35-3.25 (m, 2H), 2.46 (s, 3H), 2.43 (s, 3H), 2.40-2.24 (m, 12H), 1.55-1.27 (m, 6H).
<Example 8-42> (Z) -5-((5-hydroxy-4,6-dimethyl-2-oxo-1H-pyrrolo [2,3-b] pyridine-3 (2H) -ylidene) methyl) Production of -2,4-dimethyl-N- (2- (piperidin-1-yl) ethyl) -1H-pyrrole-3-carboxamide (I-42)
1 H-NMR ((CD 3 ) 2 SO) δ 13.54 (s, 1H), 7.48-7.42 (m, 2H), 3.35-3.25 (m, 2H), 2.46 (s, 3H), 2.43 (s, 3H ), 2.40-2.24 (m, 12H), 1.55-1.27 (m, 6H).
＜実施例８−４３＞（Ｚ）−３−（（３，５−ジメチル−４−（ピペリジン−１−カルボニル）−１Ｈ−ピロール−２−イル）メチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−４３）の製造
1H-NMR ((CD3)2SO) δ 13.46 (s, 1H), 11.09 (s, 1H), 8.21 (br s, 1H), 7.43 (s, 1H), 3.60-3.40 (m, 4H), 2.46 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H), 2.17 (s, 3H), 1.65-1.36 (m, 6H).
Example 8-43 (Z) -3-((3,5-dimethyl-4- (piperidin-1-carbonyl) -1H-pyrrol-2-yl) methylene) -5-hydroxy-4,6- Production of dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I-43)
1 H-NMR ((CD 3 ) 2 SO) δ 13.46 (s, 1H), 11.09 (s, 1H), 8.21 (br s, 1H), 7.43 (s, 1H), 3.60-3.40 (m, 4H) , 2.46 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H), 2.17 (s, 3H), 1.65-1.36 (m, 6H).
＜実施例８−４４＞（Ｚ）−３−（（３，５−ジメチル−４−（ピロリジン−１−カルボニル）−１Ｈ−ピロール−２−イル）メチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−４４）の製造
1H-NMR ((CD3)2SO) δ 13.43 (s, 1H), 11.09 (s, 1H), 8.18 (s, 1H), 7.43 (s, 1H), 3.51-3.40 (m, 2H), 3.27-3.18 (m, 2H), 2.46 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H), 1.92-1.74 (m, 4H).
<Example 8-44> (Z) -3-((3,5-dimethyl-4- (pyrrolidine-1-carbonyl) -1H-pyrrol-2-yl) methylene) -5-hydroxy-4,6- Production of dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I-44)
1 H-NMR ((CD 3 ) 2 SO) δ 13.43 (s, 1H), 11.09 (s, 1H), 8.18 (s, 1H), 7.43 (s, 1H), 3.51-3.40 (m, 2H), 3.27-3.18 (m, 2H), 2.46 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H), 1.92-1.74 (m, 4H).
＜実施例８−４５＞（Ｚ）−３−（（３，５−ジメチル−４−（４−メチルピペラジン−１−カルボニル）−１Ｈ−ピロール−２−イル）メチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−４５）の製造
1H-NMR ((CD3)2SO) δ 13.49 (s, 1H), 11.11 (s, 1H), 8.21 (br s, 1H), 7.45 (s, 1H), 3.49-3.35 (m, 4H), 2.47 (s, 3H), 2.33 (s, 3H), 2.31-2.27 (m, 7H), 2.21-2.17 (m, 6H).
<Example 8-45> (Z) -3-((3,5-dimethyl-4- (4-methylpiperazine-1-carbonyl) -1H-pyrrol-2-yl) methylene) -5-hydroxy-4 Of 6,6-dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I-45)
1 H-NMR ((CD 3 ) 2 SO) δ 13.49 (s, 1H), 11.11 (s, 1H), 8.21 (br s, 1H), 7.45 (s, 1H), 3.49-3.35 (m, 4H) , 2.47 (s, 3H), 2.33 (s, 3H), 2.31-2.27 (m, 7H), 2.21-2.17 (m, 6H).
＜実施例８−４６＞（Ｚ）−３−（（３，５−ジメチル−４−（モルホリン−４−カルボニル）−１Ｈ−ピロール−２−イル）メチレン）−５−ヒドロキシ−４，６−ジメチル−１Ｈ−ピロロ［２，３−ｂ］ピリジン−２（３Ｈ）−オン（Ｉ−４６）の製造
1H-NMR ((CD3)2SO) δ 13.49 (s, 1H), 11.10 (s, 1H), 8.19 (br s, 1H), 7.43 (s, 1H), 3.62-3.54 (m, 4H), 3.53-3.39 (m, 4H), 2.46 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 2.20 (s, 3H).
<Example 8-46> (Z) -3-((3,5-dimethyl-4- (morpholin-4-carbonyl) -1H-pyrrol-2-yl) methylene) -5-hydroxy-4,6- Production of dimethyl-1H-pyrrolo [2,3-b] pyridin-2 (3H) -one (I-46)
1 H-NMR ((CD 3 ) 2 SO) δ 13.49 (s, 1H), 11.10 (s, 1H), 8.19 (br s, 1H), 7.43 (s, 1H), 3.62-3.54 (m, 4H) , 3.53-3.39 (m, 4H), 2.46 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 2.20 (s, 3H).
＜実験例１＞細胞毒性実験
細胞毒性試験は、ＭＴＴアッセイによって測定した。各細胞株の９６ウェルプレートに１×１０４細胞／ウェルの密度で培養した。２４時間後、１％ＦＢＳ（ウシ胎仔血清）が含む培地に処理し、化合物又は化合物の溶液と４８時間反応させた。
<Experimental example 1> Cytotoxicity experiment The cytotoxicity test was measured by an MTT assay. Each cell line was cultured at a density of 1 × 10 4 cells / well in a 96-well plate. Twenty-four hours later, the cells were treated with a medium containing 1% FBS (fetal bovine serum) and reacted with the compound or the compound solution for 48 hours.
ＭＴＴ（３−（４，５−ジメチルチアゾール−２−イル）−２，５−ジフェニルテトラゾリウムブロミド）溶液（５ｍｇ／ｍＬ）を各ウェルに加え、インキュベーターで４時間反応させた。最後に、ＭＴＴ溶液が含まれた培地を捨て、細胞内に形成されたホルマザン（５−（４，５−ジメチルチアゾール−２−イル）−１，３−ジフェニルホルマザン）を溶解させるためにＤＭＳＯを添加した。インキュベーター内で３０分反応させた後、ホルマザン形成を、吸光度５４０ｎｍでマイクロプレートリーダーを利用して定量した。 MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) solution (5 mg / mL) was added to each well, and the mixture was reacted in an incubator for 4 hours. Finally, the medium containing the MTT solution is discarded, and DMSO is added to dissolve formazan (5- (4,5-dimethylthiazol-2-yl) -1,3-diphenylformazan) formed in the cells. Was added. After reacting for 30 minutes in an incubator, formazan formation was quantified using a microplate reader at an absorbance of 540 nm.
まず、化合物の癌細胞死滅に対して有効である化合物を探索するために、ＭＣＦ−７（ヒト乳癌細胞株）及びＰＡＮＣ−１（ヒト膵臓癌細胞株）を利用して各化合物を３０μＭ濃度で処理して、細胞毒性を調べた。このとき、対照群としてスニチニブ（sunitinib）を使用した。細胞毒性試験の結果を下記表２及び３に示した。 First, in order to search for compounds that are effective in killing cancer cells of the compounds, each compound was used at a concentration of 30 μM using MCF-7 (human breast cancer cell line) and PANC-1 (human pancreatic cancer cell line). Treatment and cytotoxicity studies. At this time, sunitinib (sunitinib) was used as a control group. The results of the cytotoxicity test are shown in Tables 2 and 3 below.
ＭＣＦ−７細胞に７０％以上の細胞毒性を示す化合物、スニチニブ（sunitinib）よりも優れた抑制活性を有する化合物、特に化学構造的に特に有意な化合物を選別して、８種類のヒト癌細胞株における化合物の細胞毒性ＩＣ５０を測定した。ここで用いられたヒト癌細胞株は、ＭＣＦ−７（乳癌）、ＭＤＡ−ＭＢ−２３１（乳癌）、ＨＴ−２９（結腸癌）、ＤＵ１４５（前立腺癌）、Ｕ９３７（骨髄性白血病）、Ａ５４９（肺癌）、ＰＡＮＣ−１（膵臓癌）及びＭＩＡ ＰａＣａ−２（膵臓癌）であった。測定結果は下記の表４〜１１に示した。 A compound showing cytotoxicity of 70% or more in MCF-7 cells, a compound having an inhibitory activity superior to sunitinib (especially, a compound having a particularly significant chemical structure) and eight kinds of human cancer cell lines are selected. The cytotoxic IC 50 of the compound was determined. The human cancer cell lines used here were MCF-7 (breast cancer), MDA-MB-231 (breast cancer), HT-29 (colon cancer), DU145 (prostate cancer), U937 (myeloid leukemia), A549 ( Lung cancer), PANC-1 (pancreatic cancer) and MIA PaCa-2 (pancreatic cancer). The measurement results are shown in Tables 4 to 11 below.
それぞれの癌細胞株に対して、対照薬物であるスニチニブ（sunitinib）に比べて同等以上の細胞毒性を示した化合物は、ＭＣＦ−７においてＩ−１９、Ｉ−２４、Ｉ−３９、Ｉ−４０及びＩ−４１であり、ＭＤＡ−ＭＢ−２３１においてＩ−２４、Ｉ−３９、Ｉ−４０及びＩ−４１であり、ＨＴ−２９においてＩ−２４、Ｉ−４０及びＩ−４１であり、ＤＵ−１４５においてＩ−１５、Ｉ−１７、Ｉ−１８、Ｉ−２２、Ｉ−２４、Ｉ−３９、Ｉ−４０及びＩ−４１であり、Ｕ９３７においてＩ−２４及びＩ−４１であり、Ａ−５４９においてＩ−２４、Ｉ−４０及びＩ−４１であった。膵臓癌細胞株であるＰＡＮＣ−１とＭＩＡ ＰａＣａ−２細胞株は、下記表９及び表１０示しように、ゲムシタビンに抵抗性を有していることが確認された。これら細胞株でスニチニブ（sunitinib）に比べて同等以上の細胞毒性を示した多化合物は、ＰＡＮＣ−１においてＩ−１８、Ｉ−１９、Ｉ−２４、Ｉ−３９、Ｉ−４０、Ｉ−４１及びＩ−４６であり、ＭＩＡ ＰａＣａ−２においてＩ−３９、Ｉ−４０及びＩ−４１であった。上記化合物を含む２０種の化合物の、正常細胞株であるＨＥＫ２９３（ヒト胚性腎臓細胞株）及びＣＨＯ−Ｋ１（カイコ卵巣細胞）に対する細胞毒性ＩＣ５０を測定した。測定結果を下記表１２及び表１３に示した。 For each cancer cell line, compounds showing cytotoxicity equal to or higher than that of the control drug sunitinib (sunitinib) were expressed in MCF-7 as I-19, I-24, I-39 and I-40. And I-41, MDA-MB-231, I-24, I-39, I-40, and I-41; HT-29, I-24, I-40, and I-41; At -145 are I-15, I-17, I-18, I-22, I-24, I-39, I-40 and I-41, and at U937 are I-24 and I-41; At -549, they were I-24, I-40 and I-41. As shown in Tables 9 and 10, pancreatic cancer cell lines PANC-1 and MIA PaCa-2 cell lines were confirmed to have resistance to gemcitabine. Multi-compounds showing cytotoxicity equal to or greater than sunitinib in these cell lines were found to be I-18, I-19, I-24, I-39, I-40, I-41 in PANC-1. And I-46, and I-39, I-40 and I-41 in MIA PaCa-2. The cytotoxic IC 50 of 20 compounds including the above compounds was measured on normal cell lines HEK293 (human embryonic kidney cell line) and CHO-K1 (silkworm ovary cells). The measurement results are shown in Tables 12 and 13 below.
ＨＥＫ２９３及びＣＨＯ−Ｋ１細胞で２０種の化合物全てが、スニチニブ（sunitinib）よりも高いＩＣ５０値を示し、これらがスニチニブ（sunitinib）よりも安全な化合物であることを確認した。
（産業上利用の可能性）
本発明による７−アザインドリン−２−オン誘導体又はその薬学的許容される塩は、癌の成長抑制剤及び癌転移抑制用薬剤として好適に用いることができる。
(Possibility of industrial use)
The 7-azaindoline-2-one derivative or a pharmaceutically acceptable salt thereof according to the present invention can be suitably used as a cancer growth inhibitor and a cancer metastasis inhibitor.
Claims (11)
Ｒ２及びＲ３は、それぞれ独立して、炭素数１〜４のアルキルであり、
Ｒ６は、水素；炭素数１〜１２のアルキル；炭素数２〜１２のアルケニル；炭素数６〜１２のアリール；及びヘテロ原子が１〜３個含まれた炭素数３〜１２のヘテロアリールからなる群から選ばれたいずれか一つであり、
ここで、前記炭素数１〜１２のアルキル又は炭素数２〜１２のアルケニルは、炭素数６〜１２のアリールで置換され又は置換されておらず、
前記炭素数６〜１２のアリールは、ハロゲン；−ＮＯ２；炭素数１〜４のアルキル；−ＯＲ１１；及び−ＮＲ２０Ｒ２１からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
前記炭素数３〜１２のヘテロアリールは、炭素数１〜４のアルキル；−Ｃ（Ｏ）Ｒ１４；−Ｃ（Ｏ）ＯＲ１５；及び−Ｃ（Ｏ）ＮＲ２２Ｒ２３からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
Ｒ１１、Ｒ１４及びＲ１５は、それぞれ独立して、水素；及び炭素数１〜４のアルキルからなる群から選ばれたいずれか一つであり、
Ｒ２０〜Ｒ２３は、それぞれ独立して、水素；及び炭素数１〜６のアルキルからなる群から選ばれたいずれか一つであるか、又はＲ２２及びＲ２３は、共に、ヘテロ原子が１〜３個含まれた炭素数３〜８のヘテロアリール、又は共にメチルで置換された又は置換されていないピペラジン、ピペリジン、ピロリジン、又はモルホリンを形成してもよく、
ここで、Ｒ１１、Ｒ１４、Ｒ１５、及びＲ２０〜Ｒ２３の炭素数１〜４のアルキル及び炭素数３〜８のヘテロアリールは、それぞれ独立して、炭素数１〜４のアルキル；及び−ＮＲ２４Ｒ２５からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
Ｒ２４及びＲ２５は、それぞれ独立して、水素；及び炭素数１〜４のアルキルからなる群から選ばれたいずれか一つであるか、又はＲ２４及びＲ２５は、共に、ヘテロ原子が１〜３個含まれた炭素数３〜８のヘテロアリールを形成してもよい。］ A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
R 2 and R 3 are each independently alkyl having 1 to 4 carbons;
R 6 is hydrogen; alkyl having 1 to 12 carbons; alkenyl having 2 to 12 carbons; aryl having 6 to 12 carbons; and heteroaryl having 3 to 12 carbons containing 1 to 3 heteroatoms. One of the group
Here, the alkyl having 1 to 12 carbons or the alkenyl having 2 to 12 carbons is substituted or unsubstituted with aryl having 6 to 12 carbons,
The aryl having 6 to 12 carbon atoms is substituted with one or more substituents selected from the group consisting of halogen; -NO 2 ; alkyl having 1 to 4 carbon atoms; -OR 11 ; and -NR 20 R 21. Or not replaced,
Heteroaryl of said 3 to 12 carbon atoms, alkyl of 1 to 4 carbon atoms; selected from the group consisting of and -C (O) NR 22 R 23 ; -C (O) R 14; -C (O) OR 15 Substituted or unsubstituted with one or more substituents
R 11 , R 14 and R 15 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 4 carbon atoms;
R 20 to R 23 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 6 carbon atoms, or R 22 and R 23 both have a hetero atom. 1 to 3 heteroaryls having 3 to 8 carbon atoms , or both piperazine, piperidine, piperidine, pyrrolidine, or morpholine substituted or unsubstituted with methyl ,
Here, R 11 , R 14 , R 15 , and R 20 to R 23 alkyl having 1 to 4 carbon atoms and heteroaryl having 3 to 8 carbon atoms are each independently an alkyl having 1 to 4 carbon atoms; And -NR 24 R 25 is substituted or unsubstituted with one or more substituents selected from the group consisting of:
R 24 and R 25 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 4 carbon atoms, or R 24 and R 25 both have a heteroatom 1 to 3 heteroaryl having 3 to 8 carbon atoms may be formed. ]
水素；
ＯＨ及びメトキシからなる群から選ばれた一つ以上の置換基で置換された又は置換されていない炭素数６〜１２のアリールで置換された又は置換されていない炭素数１〜１２のアルキル又は炭素数２〜１２のアルケニル；
ハロゲン、−ＮＯ２、ＯＨ、メトキシ、メチル、エチル、プロピル、メチルアミン、エチルアミン、ジメチルアミン及びジエチルアミンからなる群から選ばれた一つ以上の置換基で置換された又は置換されていない炭素数６〜１２のアリール；又は
メチル；エチル；−Ｃ（Ｏ）ＯＲ１５；及び−Ｃ（Ｏ）ＮＲ２２Ｒ２３からなる群から選ばれた一つ以上の置換基で置換された又は置換されていない、ヘテロ原子が１〜３個含まれた炭素数３〜１２のヘテロアリールを表し、
Ｒ１５は、水素、メチル又はエチルを表し、
Ｒ２２及びＲ２３は、それぞれ独立して、水素；又はメチルアミン、エチルアミン、ジメチルアミン、ジエチルアミン及びピペリジンからなる群から選ばれた一つ以上の置換基で置換された又は置換されていないメチル又はエチルを表すか、又はＲ２２及びＲ２３は、共に、メチルで置換された又は置換されていないピペラジン、ピペリジン、ピロリジン、又はモルホリンを形成してもよい、請求項１に記載の化合物又はその薬学的に許容される塩。 R 6 is
hydrogen;
Alkyl or carbon having 1 to 12 carbon atoms substituted or unsubstituted with aryl having 6 to 12 carbon atoms substituted or unsubstituted with one or more substituents selected from the group consisting of OH and methoxy Alkenyl of the formulas 2 to 12;
Halogen, -NO 2, OH, methoxy, methyl, ethyl, propyl, methylamine, ethylamine, carbon atoms not been or substituted substituted by one or more substituents selected from the group consisting of dimethylamine and diethylamine 6 -C (O) OR < 15 >; and -C (O) NR < 22 > R < 23 > substituted or unsubstituted with one or more substituents selected from the group consisting of: Represents a heteroaryl having 3 to 12 carbon atoms containing 1 to 3 heteroatoms,
R 15 represents hydrogen, methyl or ethyl;
R 22 and R 23 are each independently hydrogen; or methyl substituted or unsubstituted with one or more substituents selected from the group consisting of methylamine, ethylamine, dimethylamine, diethylamine and piperidine. or represents ethyl, or R 22 and R 23 are both methyl in substituted or substituted optionally a Ipi Perazine, piperidine, pyrrolidine, or morpholine may form, a compound according to claim 1 or Its pharmaceutically acceptable salts.
一つ以上のフェニルで置換された又は置換されていない炭素数１〜８のアルキル；
ＯＨ及びメトキシからなる群から選ばれた一つ以上の置換基で置換された又は置換されていないフェニルで置換された又は置換されていない炭素数２〜８のアルケニル；
ハロゲン、−ＮＯ２、ＯＨ、メトキシ、メチル、エチル、ジメチルアミン、ジエチルアミンからなる群から選ばれた一つ以上の置換基で置換された又は置換されていない炭素数６〜１０のアリール；又は
メチル；エチル；−Ｃ（Ｏ）ＯＲ１５；及び−Ｃ（Ｏ）ＮＲ２２Ｒ２３からなる群から選ばれた一つ以上の置換基で置換された又は置換されていない、ヘテロ原子が１〜３個含まれた炭素数３〜１０のヘテロアリールを表し、
Ｒ１５は、水素、メチル又はエチルを表し、
Ｒ２２及びＲ２３は、それぞれ独立して、水素；又はメチルアミン、エチルアミン、ジメチルアミン、ジエチルアミン及びピペリジンからなる群から選ばれた一つ以上の置換基で置換された又は置換されていないメチル又はエチルを表すか、又はＲ２２及びＲ２３は、共に、メチルで置換された又は置換されていないピペラジン、ピペリジン、ピロリジン、又はモルホリンを形成してもよい、請求項１に記載の化合物又はその薬学的に許容される塩。 R 6 is
C1-C8 alkyl substituted or unsubstituted with one or more phenyl;
C2-C8 alkenyl substituted or unsubstituted with phenyl substituted or unsubstituted with one or more substituents selected from the group consisting of OH and methoxy;
Halogen, -NO 2, OH, methoxy, methyl, ethyl, dimethylamine, having 6 to 10 carbon atoms that are not the or substituted substituted by one or more substituents selected from the group consisting of diethylamine aryl; or methyl Ethyl; —C (O) OR 15 ; and —C (O) NR 22 R 23 , wherein the heteroatom is substituted or unsubstituted with one or more substituents selected from the group consisting of 1 to 3; Represents a heteroaryl having 3 to 10 carbon atoms,
R 15 represents hydrogen, methyl or ethyl;
R 22 and R 23 are each independently hydrogen; or methyl substituted or unsubstituted with one or more substituents selected from the group consisting of methylamine, ethylamine, dimethylamine, diethylamine and piperidine. or represents ethyl, or R 22 and R 23 are both methyl in substituted or substituted optionally a Ipi Perazine, piperidine, pyrrolidine, or morpholine may form, a compound according to claim 1 or Its pharmaceutically acceptable salts.
Ｒ２及びＲ３は、それぞれ独立して、炭素数１〜４のアルキルであり、
Ｒ６は、水素；炭素数１〜１２のアルキル；炭素数２〜１２のアルケニル；炭素数６〜１２のアリール；及びヘテロ原子が１〜３個含まれた炭素数３〜１２のヘテロアリールからなる群から選ばれたいずれか一つであり、
ここで、前記炭素数１〜１２のアルキル又は炭素数２〜１２のアルケニルは、炭素数６〜１２のアリールで置換され又は置換されておらず、
前記炭素数６〜１２のアリールは、ハロゲン；−ＮＯ２；炭素数１〜４のアルキル；−ＯＲ１１；及び−ＮＲ２０Ｒ２１からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
前記炭素数３〜１２のヘテロアリールは、炭素数１〜４のアルキル；−Ｃ（Ｏ）Ｒ１４；−Ｃ（Ｏ）ＯＲ１５；及び−Ｃ（Ｏ）ＮＲ２２Ｒ２３からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
Ｒ１１、Ｒ１４及びＲ１５は、それぞれ独立して、水素；及び炭素数１〜４のアルキルからなる群から選ばれたいずれか一つであり、
Ｒ２０〜Ｒ２３は、それぞれ独立して、水素；及び炭素数１〜６のアルキルからなる群から選ばれたいずれか一つであるか、又はＲ２２及びＲ２３は、共に、ヘテロ原子が１〜３個含まれた炭素数３〜８のヘテロアリールを形成してもよく、
ここで、Ｒ１１、Ｒ１４、Ｒ１５、及びＲ２０〜Ｒ２３の炭素数１〜４のアルキル及び炭素数３〜８のヘテロアリールは、それぞれ独立して、炭素数１〜４のアルキル；及び−ＮＲ２４Ｒ２５からなる群から選ばれた一つ以上の置換基で置換され又は置換されておらず、
Ｒ２４及びＲ２５は、それぞれ独立して、水素；及び炭素数１〜４のアルキルからなる群から選ばれたいずれか一つであるか、又はＲ２４及びＲ２５は、共に、ヘテロ原子が１〜３個含まれた炭素数３〜８のヘテロアリールを形成してもよい。］ A method for producing a compound of the following formula (1) by reacting a compound of the following formula (2) with a compound of the following formula (3):
R 2 and R 3 are each independently alkyl having 1 to 4 carbons;
R 6 is hydrogen; alkyl having 1 to 12 carbons; alkenyl having 2 to 12 carbons; aryl having 6 to 12 carbons; and heteroaryl having 3 to 12 carbons containing 1 to 3 heteroatoms. One of the group
Here, the alkyl having 1 to 12 carbons or the alkenyl having 2 to 12 carbons is substituted or unsubstituted with aryl having 6 to 12 carbons,
The aryl having 6 to 12 carbon atoms is substituted with one or more substituents selected from the group consisting of halogen; -NO 2 ; alkyl having 1 to 4 carbon atoms; -OR 11 ; and -NR 20 R 21. Or not replaced,
Heteroaryl of said 3 to 12 carbon atoms, alkyl of 1 to 4 carbon atoms; selected from the group consisting of and -C (O) NR 22 R 23 ; -C (O) R 14; -C (O) OR 15 Substituted or unsubstituted with one or more substituents
R 11 , R 14 and R 15 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 4 carbon atoms;
R 20 to R 23 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 6 carbon atoms, or R 22 and R 23 both have a hetero atom. May form a heteroaryl having 1 to 3 carbon atoms having 3 to 8 carbon atoms,
Here, R 11 , R 14 , R 15 , and R 20 to R 23 alkyl having 1 to 4 carbon atoms and heteroaryl having 3 to 8 carbon atoms are each independently an alkyl having 1 to 4 carbon atoms; And -NR 24 R 25 is substituted or unsubstituted with one or more substituents selected from the group consisting of:
R 24 and R 25 are each independently any one selected from the group consisting of hydrogen; and alkyl having 1 to 4 carbon atoms, or R 24 and R 25 both have a heteroatom 1 to 3 heteroaryl having 3 to 8 carbon atoms may be formed. ]
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20150158695 | 2015-11-12 | ||
| KR10-2015-0158695 | 2015-11-12 | ||
| PCT/KR2016/012409 WO2017082569A1 (en) | 2015-11-12 | 2016-10-31 | Pharmaceutical composition containing, as active ingredient, 7-azaindolin-2-one derivative or pharmaceutically acceptable salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2018533600A JP2018533600A (en) | 2018-11-15 |
| JP6661766B2 true JP6661766B2 (en) | 2020-03-11 |
Family
ID=58695675
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2018524367A Active JP6661766B2 (en) | 2015-11-12 | 2016-10-31 | Pharmaceutical composition containing a 7-azaindoline-2-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US10544140B2 (en) |
| EP (1) | EP3363799A4 (en) |
| JP (1) | JP6661766B2 (en) |
| KR (1) | KR102109869B1 (en) |
| CN (1) | CN108368108B (en) |
| AU (1) | AU2016353573B2 (en) |
| BR (1) | BR112018009482A2 (en) |
| CA (1) | CA3004595A1 (en) |
| CL (1) | CL2018001236A1 (en) |
| CO (1) | CO2018005367A2 (en) |
| EA (1) | EA201891136A1 (en) |
| IL (1) | IL259083A (en) |
| MA (1) | MA42361A1 (en) |
| MX (1) | MX2018005894A (en) |
| NZ (1) | NZ742228A (en) |
| PH (1) | PH12018500946A1 (en) |
| WO (1) | WO2017082569A1 (en) |
| ZA (1) | ZA201803722B (en) |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9721437D0 (en) * | 1997-10-10 | 1997-12-10 | Glaxo Group Ltd | Heteroaromatic compounds and their use in medicine |
| WO2000008202A2 (en) * | 1998-08-04 | 2000-02-17 | Sugen, Inc. | 3-methylidenyl-2-indolinone modulators of protein kinase |
| EP1244672B1 (en) * | 1999-12-21 | 2005-07-20 | Sugen, Inc. | 4-substituted 7-aza-indolin-2-ones and their use as protein kinase inhibitors |
| CN102066362B (en) * | 2008-05-23 | 2014-07-30 | 上海医药工业研究院 | Dihydroindolinone derivatives |
| ES2748873T3 (en) * | 2012-01-26 | 2020-03-18 | Angion Biomedica Corp | Antifibrotic compounds and uses thereof |
| WO2014085795A1 (en) * | 2012-11-30 | 2014-06-05 | University Of Rochester | Mixed lineage kinase inhibitors for hiv/aids therapies |
| SG11201507346PA (en) * | 2013-03-13 | 2015-10-29 | Boston Biomedical Inc | 3-(aryl or heteroaryl) methyleneindolin-2-one derivatives as inhibitors of cancer stem cell pathway kinases for the treatment of cancer |
| US9187454B2 (en) * | 2013-03-13 | 2015-11-17 | Boston Biomedical, Inc. | Inhibitors of kinases and cancer stem cells, and methods of preparation and use thereof |
| CN104876928B (en) * | 2015-05-07 | 2016-09-14 | 浙江司太立制药股份有限公司 | 7-azaindole quinoline-2-ketone compounds and preparation method thereof |
-
2016
- 2016-10-31 NZ NZ74222816A patent/NZ742228A/en not_active IP Right Cessation
- 2016-10-31 MA MA42361A patent/MA42361A1/en unknown
- 2016-10-31 EP EP16864495.3A patent/EP3363799A4/en not_active Withdrawn
- 2016-10-31 JP JP2018524367A patent/JP6661766B2/en active Active
- 2016-10-31 EA EA201891136A patent/EA201891136A1/en unknown
- 2016-10-31 WO PCT/KR2016/012409 patent/WO2017082569A1/en active Application Filing
- 2016-10-31 AU AU2016353573A patent/AU2016353573B2/en not_active Expired - Fee Related
- 2016-10-31 BR BR112018009482-0A patent/BR112018009482A2/en not_active Application Discontinuation
- 2016-10-31 CA CA3004595A patent/CA3004595A1/en active Pending
- 2016-10-31 US US15/775,312 patent/US10544140B2/en active Active
- 2016-10-31 MX MX2018005894A patent/MX2018005894A/en unknown
- 2016-10-31 CN CN201680066277.1A patent/CN108368108B/en active Active
- 2016-10-31 KR KR1020160143677A patent/KR102109869B1/en active IP Right Grant
-
2018
- 2018-05-01 IL IL259083A patent/IL259083A/en unknown
- 2018-05-03 PH PH12018500946A patent/PH12018500946A1/en unknown
- 2018-05-08 CL CL2018001236A patent/CL2018001236A1/en unknown
- 2018-05-23 CO CONC2018/0005367A patent/CO2018005367A2/en unknown
- 2018-06-05 ZA ZA2018/03722A patent/ZA201803722B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN108368108B (en) | 2021-09-21 |
| IL259083A (en) | 2018-06-28 |
| MX2018005894A (en) | 2018-08-15 |
| NZ742228A (en) | 2019-09-27 |
| CL2018001236A1 (en) | 2018-08-24 |
| EP3363799A1 (en) | 2018-08-22 |
| EP3363799A4 (en) | 2018-12-05 |
| CN108368108A (en) | 2018-08-03 |
| JP2018533600A (en) | 2018-11-15 |
| CO2018005367A2 (en) | 2018-06-12 |
| EA201891136A1 (en) | 2018-10-31 |
| MA42361A1 (en) | 2018-09-28 |
| WO2017082569A1 (en) | 2017-05-18 |
| PH12018500946A1 (en) | 2018-11-12 |
| AU2016353573B2 (en) | 2019-11-21 |
| BR112018009482A2 (en) | 2018-11-06 |
| CA3004595A1 (en) | 2017-05-18 |
| KR20170056430A (en) | 2017-05-23 |
| US20180370964A1 (en) | 2018-12-27 |
| ZA201803722B (en) | 2019-03-27 |
| US10544140B2 (en) | 2020-01-28 |
| AU2016353573A1 (en) | 2018-05-24 |
| KR102109869B1 (en) | 2020-05-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2733750C2 (en) | Derivatives of carboxy-substituted (hetero)aromatic rings, method of synthesis and use thereof | |
| US8304408B2 (en) | Wnt signaling inhibitors, and methods for making and using them | |
| JP5808408B2 (en) | Phthalazinone ketone derivative, its production method and pharmaceutical use | |
| CN114846005B (en) | SHP2 inhibitor and application thereof | |
| CN101678214B (en) | Aryl ether pyridazinone derivatives | |
| EA022029B1 (en) | Thienopyrimidinedione derivatives as trpa1 modulators | |
| CN101312956A (en) | Substituted 5-phenyl-3,6-dihydro-2-oxo-6H-[1,3,4]thiadiazines | |
| US8871802B2 (en) | Naphthoquinones for disease therapies | |
| TW200904436A (en) | Arylamide pyrimidone derivatives | |
| WO2011124087A1 (en) | Oxadiazole-based piperazine derivatives and applications thereof | |
| JP6930060B2 (en) | Novel dihydropyranopyrimidinone derivatives and their uses {Novell dihydropyranopylidinone derivatives, and use thetheof} | |
| JP6661766B2 (en) | Pharmaceutical composition containing a 7-azaindoline-2-one derivative or a pharmaceutically acceptable salt thereof as an active ingredient | |
| WO2021018173A1 (en) | Adenosine receptor antagonist | |
| WO2018086609A1 (en) | 3,4-bipyridyl pyrazole derivative, and preparation method therefor and medical application thereof | |
| WO2021017880A1 (en) | Class of triaromatic compounds targeting bifunctional phosphorylation site of stat3 and applications thereof | |
| WO2023066371A1 (en) | Nitrogen-containing tetracyclic compound, preparation method therefor, and medical use thereof | |
| CN112574212B (en) | Pyrimido five-membered nitrogen heterocyclic derivative, preparation method and medical application thereof | |
| US11464770B2 (en) | Anticancer pharmaceutical composition | |
| CN109206435B (en) | Thieno [3,2-d ] pyrimidine compound and preparation method and medical application thereof | |
| WO2010134082A1 (en) | Chromenone derivatives for treatment of cancer | |
| WO2021018172A1 (en) | Adenosine receptor antagonist | |
| KR102649886B1 (en) | Novel pyrimidine-4-one compound and anticancer composition comprising the same | |
| ES2746064T3 (en) | Aminomethylene pyrazolones with therapeutic activity | |
| CN114853746A (en) | Formamide compound, preparation method and medical application thereof | |
| KR20240019078A (en) | Urea derivatives for treating uveal melanoma |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180627 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20190307 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190325 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190620 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190823 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200114 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200212 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6661766 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
| R360 | Written notification for declining of transfer of rights |
Free format text: JAPANESE INTERMEDIATE CODE: R360 |
|
| R360 | Written notification for declining of transfer of rights |
Free format text: JAPANESE INTERMEDIATE CODE: R360 |
|
| R371 | Transfer withdrawn |
Free format text: JAPANESE INTERMEDIATE CODE: R371 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |